Dihydropyridine derivatives and process for preparing the same

ABSTRACT

Dihydropyridine derivatives and salts thereof represented by the general formula, ##STR1## which possess excellent calcium antagonist effect, hypotensive effect, platelets aggregation inhibitory effect, phosphodiesterase inhibitory effect, calmodulin inhibitory effect and peroxidized lipid lowering effect, and thus dihydropyridine derivatives and salts thereof are useful as a coronary blood flow improving agent such as coronary vasodilator, hypotensive agent, prophylaxis and treating agents for thrombosis, phosphodiesterase inhibitory agent, peroxidized lipid metabolism lowering agent, anti-inflammatory agent and others.

This is a division of Ser. No. 07/018,836, filed Feb. 24, 1987, now U.S.Pat. No. 5,034,395, which is a continuation of Ser. No. 06/677,364,filed Nov. 30, 1984, now abandoned.

FIELD OF THE INVENTION

The present invention relates to dihydropyridine derivatives and saltsthereof More particularly, the present invention relates todihydropyridine derivatives and salts thereof, process for preparing thesame, as well as pharmaceutical composition containing the same as theactive ingredient.

The dihydropyridine derivatives and salts thereof are novel compounds,and are not known in any of prior art references The dihydropyridinederivatives and salts thereof according to the present invention arerepresented by the general formula (1), ##STR2## wherein R¹ and R⁴ areeach a lower alkyl group; R² is a lower alkyl group or a group of theformula --CH₂ --A--R⁶ [wherein A is a straight-chain or branched-chainunsaturated group hydrocarbon group which may have an oxygen atom or agroup of the formula ##STR3## (wherein R⁷ is a lower alkyl group); andR⁶ is a phenyl group which may have a hydroxyl group]; R³ is a phenylgroup which may have 1 to 2 substituents selected from the groupconsisting of a nitro group, a lower alkyl group which may have 1 to 3halogen atoms, a lower alkoxy group and a halogen atom; and R5 is alower alkyl group, a 1,2,3,6-tetrahydropyridyl-lower alkyl group whichmay have, as the substituent, a phenyl group which may have halogenatoms or lower alkyl groups as the substituents on the phenyl ring, or agroup of the formula --CH₂ --A'--R⁸ [wherein A' is a straight-chain orbranched-chain unsaturated hydrocarbon group which may have or may nothave an oxygen atom, a sulfur atom, a group of the formula ##STR4##(wherein R⁷ is a lower alkyl group) or a group of the formula ##STR5##in the unsaturated hydrocarbon group; and R⁸ is a phenyl group which mayhave 1 to 3 substituents selected from the group consisting of a loweralkoxy group, a halogen atom, a lower alkylthio group, a hydroxyl group,a lower alkanoyloxy group, a tetrahydropyranyloxy group and a loweralkoxy-lower alkoxy group; a pyridyl group; a thienyl group; furylgroup, or a tetrazolyl group which may have a lower alkyl group as thesubstituent]; provided that when R⁵ is a lower alkyl group, then R²should be a group of the formula --CH₂ --A--R⁶ (wherein A and R⁶ are thesame as defined above).

Dihydropyridine derivatives and salts thereof represented by the generalformula (1) possess excellent calcium antagonist effect, hypotensiveeffect, platelets aggregation inhibitory effect, phosphodiesteraseinhibitory effect, calmodulin inhibitory effect and peroxidized lipidlowering effect, and thus the dihydropyridine derivative and saltthereof represented by the general formula (1) are useful as a coronaryblood flow improving agent such as coronary vasodilator, hypotensiveagent, prophylaxis and treating agents for thrombosis, phosphodiesteraseinhibitory agent, peroxidized lipid metabolism lowering agent,anti-inflammatory agent and others.

DESCRIPTION OF THE PRIOR ART

Compounds similar to the dihydropyridine derivatives according to thepresent invention are known from the disclosures in Japanese PatentApplication Kokai (Laid-open) No. 51-108075 (1976) and Japanese PatentApplication Kokai (Laid-open) No. 56-36455 (1981). Compounds of theseprior art references are known as useful hypotensive agents, peripheraland cerebral vasodilating agents and treating agent for coronary bloodvessels. On the contrary, dihydropyridine derivatives according to thepresent invention have features in that they perform theirpharmacological effects for longer period of time with less side-effectsas compared with known compounds. Furthermore, dihydropyridinederivatives according to the present invention are useful ascarcinostatic agents.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel dihydropyridinederivatives.

Another object of the present invention is to provide process forpreparing said dihydropyridine derivatives.

Further object of the present invention is to provide a pharamceuticalcomposition containing said dihydropyridine derivative as the activeingredient.

These and other objects and features of the present invention willbecome more fully apparent from the following description.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Dihydropyridine derivatives represented by the general formula (1)according to the present invention, examples of various substituents asdefined in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, A and A' are as follows.

As to the lower alkyl group, an alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,hexyl groups and others can be exemplified.

As to the lower alkyl group which may have halogen atoms as thesubstituents, an alkyl group having 1 to 6 carbon atoms which may have 1to 3 halogen atoms as the substituents, in addition to theabove-mentioned alkyl groups having 1 to 6 carbon atoms,trifluoromethyl, 2,2-difluoroethyl, 1,1-dichloroethyl, trichloromethyl,dichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl,3,3,3-trichloropropyl, 3-fluoropropyl, 4-chlorobutyl,3-chloro-2-methylethyl groups and others can be exemplified

As to the lower alkoxy group, an alkoxy group having 1 to 6 carbon atomssuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,pentyloxy, hexyloxy groups and others can be exemplified.

As to the halogen atom, fluorine atom, chlorine atom, bromine atom andiodine atom can be exemplified

As to the lower alkoxy-lowered alkoxy group, an alkoxyalkoxy group ofwhich the alkoxy moieties having 1 to 6 carbon atoms such asmethoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy,4-methoxybutoxy, 1,1-dimethyl-2-methoxyethoxy, 5-methoxypentyloxy,6-methoxyhexyloxy, 2-methyl-3-methoxypropoxy, ethoxymethoxy,3-ethoxypropoxy, 6-ethoxyhexyloxy, 2-propoxyethoxy, 4-propoxybutoxy,5-butoxypentyloxy, pentyloxymethoxy, 1-pentyloxyethoxy,1,1-dimethyl-2-hexyloxyethoxy, 3-hexyloxypropoxy groups and others canbe exemplified.

As to the lower alkylthio group, an alkylthio group having 1 to 6 carbonatoms, such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, tert-butylthio, pentylthio, hexylthio groups and others canbe exemplified.

As to the lower alkanoyloxy group, an alkanoyloxy group having 1 to 6carbon atoms, such as formyloxy, acetyloxy, propionyloxy, butyryloxyisobutyryloxy, pentanoyloxy, tert- butyryloxy, hexanoyloxy groups andothers can be exemplified.

As to the phenyl group which may have 1 to 3 substituents selected fromthe group consisting of a lower alkoxy group, a halogen atom, a loweralkylthio group, a hydroxyl group, a lower alkanoyloxy group, atetrahydropyranyloxy group and a lower alkoxy-lower alkoxy group, aphenyl group which may have 1 to 3 substituents selected from the groupconsisting of an alkoxy group having 1 to 6 carbon atoms, a halogenatom, an alkylthio group having 1 to 6 carbon atoms, a hydroxyl group,an alkanoyloxy group having 1 to 6 carbon atoms, a tetrahydropyranyloxygroup and an alkoxyalkoxy group of which alkoxy moieties having 1 to 6carbon atoms, such as phenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or4-fluorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl,3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,5-dibromophenyl, 2-, 3 - or 4-methylthiophenyl,2-, 3- or 4-ethylthiophenyl, 4-propylthiophenyl, 3-isopropylthiophenyl,2-butylthiophenyl, 4-hexylthiophenyl, 3-pentylthiophenyl,4-tert-butylthiophenyl, 3,4-dimethylthiophenyl, 2,5-dimethylthiophenyl,2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 3-propoxyphenyl,4-isopropoxyphenyl, 3-butoxyphenyl, 2-pentyloxyphenyl,4-tert-butoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2-, 3- or4-(2-tetrahydropyranyloxy)phenyl, 2,4-bis(2-tetrahydropyranyloxy)phenyl,3-methylthio-4-chlorophenyl, 2-chloro-6-methylthiophenyl,2-methoxy-3-hydroxyphenyl, 3,4,5-trimethoxyphenyl,3,4,5-trimethylthiophenyl, 3,4,5-trichlorophenyl, 2-, 3- or4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2,6-dihydroxyphenyl,3,4,5-trihydroxyphenyl, 2-, 3- or 4-acetyloxyphenyl,4-propionyloxyphenyl, 3-isopropionyloxyphenyl, 2-butyryloxyphenyl,4-hexanoyloxyphenyl, 3-pentanoyloxyphenyl, 4-tert-butyryloxyphenyl,3,4-diacetyloxyphenyl, 2,5-diacetyloxyphenyl,3,4,5-tridiacetyloxyphenyl, 2-methoxymethoxyphenyl,3-(2-methoxyethoxy)phenyl, 4-(1-methoxyethoxy)phenyl,2-(3-methoxypropoxy)phenyl, 3-(4-methoxybutoxy)phenyl,4-(1,1-dimethyl-2-methoxyethoxy)phenyl, 2-(5-methoxypentyloxy)phenyl,3-(6-methoxyhexyloxy)phenyl, 4-(2-methyl-3-methoxypropoxy)phenyl,2-(ethoxymethoxy)phenyl, 3-(3-ethoxypropoxy)phenyl,4-(6-ethoxyhexyloxy)phenyl, 2-(2-propoxyethoxy)phenyl,3-(4-propoxybutoxy)phenyl, 4-(5-butoxypentyloxy)phenyl,2-(pentyloxymethoxy)phenyl, 3-(1-pentyloxyethoxy)phenyl,4-(1,1-dimethyl-2-hexyloxyethoxy)phenyl, 2-(3-hexyloxypropoxy)phenyl,2-(3-hexyloxypropoxy)phenyl groups and others can be exemplified.

As to the phenyl group which may have 1 to 2 substituents selected fromthe group consisting of a nitro group, a lower alkyl group which mayhave 1 to 3 halogen atoms, a lower alkoxy group and a halogen atom, aphenyl group which may have 1 to 2 substituents, on the phenyl ringselected from the group consisting of a nitro group, an alkyl grouphaving 1 to 6 carbon atoms which may have 1 to 3 halogen atoms, analkoxy group having 1 to 6 carbon atoms, and a halogen atom, such as aphenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or4-bromophenyl, 2-, 3- or 4-iodophenyl, 3,5-dichlorophenyl,2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,3,4-difluorophenyl, 3,5-dibromophenyl, 2-, 3- or 4-nitrophenyl,2,4-dinitrophenyl, 2,6-dinitrophenyl, 3,4-dinitrophenyl,3,5-dinitrophenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl,3-propoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 2-pentyloxyphenyl,4-tert-butoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2-, 3- or 4-methylphenyl, 2-,3- or 4-ethylphenyl, 4-propylphenyl, 3-isopropylphenyl, 2-butylphenyl,4-hexylphenyl, 3-pentylphenyl, 4-tert-butylphenyl, 3,4-dimethylphenyl,2,5-dimethylphenyl, 2-(trifluoromethyl)phenyl,3-(2,3-difluoroethyl)phenyl, 4-(1,1-dichloroethyl)phenyl,3-(trichloromethyl)phenyl, 2-(dichloromethyl)phenyl,4-(tribromomethyl)phenyl, 3-(2,2,2-trifluoroethyl)phenyl,2-(2-chloroethyl)phenyl, 4-(1,2-dichloroethyl)phenyl,3-(3,3,3-trichloropropyl)phenyl, 4-(3-chloro-2-methylethyl)phenyl,3-(4-chlorobutyl)phenyl, 2-(3-fluoropropyl)phenyl,3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl and2-methoxy-3-nitrophenyl groups and others can be exemplified.

As to the 1,2,4,6-tetrahydropyridyl-lower alkyl group which may have, asthe substituent, a phenyl group which may have halogen atoms or loweralkyl groups as the substituents on the phenyl ring, a1,2,3,6-tetrahydropyridyl group substituted-alkyl group having 1 to 6carbon atoms in the alkyl moiety, which may have as the substituent, aphenyl group which may have halogen atoms or alkyl groups having 1 to 6carbon atoms, as the substituents on the phenyl ring, such as1,2,3,6-tetrahydropyridylmethyl, 2-(1,2,3,6-tetrahydropyridyl)ethyl,1-(1,2,3,6-tetrahydropyridyl)ethyl, 3-(1,2,3,6-tetrahydropyridyl)propyl,4-(1,2,3,6-tetrahydropyridyl)butyl,1,1-dimethyl-2(1,2,3,6-tetrahydropyridyl)ethyl,5-(1,2,3,6-tetrahydropyridyl)pentyl, 6-[1,2,3,6-tetrahydropyridyl)hexyl,2-methyl-3-(1,2,3,6-tetrahydropyridyl)propyl,(4-phenyl-1,2,3,6-tetrahydropyridyl)methyl,2-[4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridyl]ethyl,1-[4-(3-bromophenyl)-1,2,3,6-tetrahydropyridyl]ethyl,3-[3-(4-chlorophenyl)-1,2,3,6-tetrahydropyridyl]propyl,[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridyl]methyl,[4-(4-methylphenyl)-1,2,3,6-tetrahydropyridyl]methyl,[4-(2-(2-ethylphenyl)-1,2,3,6-tetrahydropyridyl]methyl,1,1-dimethyl-2-[3-(3-propylphenyl)-1,2,3,6-tetrahydropyridyl]ethyl,5-[2-(2-tert-butylphenyl)- 1,2,3,6-tetrahydropyridyl]pentyl,6-[3-(4-pentylphenyl)-1,2,3,6-tetrahydropyridyl]hexyl, and2-methyl-3-[4-(3-hexylphenyl)-1,2,3,6-tetrahydropyridyl]propyl groupsand others can be exemplified.

As to the straight-chain or branched-chain unsaturated hydrocarbonresidual group which may have or may not have an oxygen atom, a sulfuratom, a group of the formula ##STR6## (wherein R⁷ is a lower alkylgroup) or a group of the formula ##STR7## in the unsaturated hydrocarbonresidual group, a straight-chain or branched-chain unsaturatedhydrocarbon residual group having 2 to 6 carbon atoms in the unsaturatedhydrocarbon residual moiety, having 1 to 3 double bonds and/or triplebonds therein, said unsaturated hydrocarbon residual group may have ormay not have an oxygen atom, a sulfur atom, a group of the formula##STR8## (wherein R⁷ is an alkyl group having 1 to 6 carbon atoms), or agroup of the formula ##STR9## such as vinylene, 1-propenylene,1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene,2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene,3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene,2-penten-4-ylene, 2-hexenylene, 1-hexenylene, 5-hexenylene,3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene,2-ethyl-1-propenylene, ethynylene, 2-propynylene, 1-propynylene,1,1-dimethyl-2-propynylene, 3,3-dimethyl-1-propynylene, 2-butynylene,3-butenylene, 1-butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene,4-pentynylene, 2-hexynylene, 1-hexynylene, 3-hexynylene, 4-hexynylene,5-hexynylene, 1,3-hexadienylene, 1,4-hexadienylene,1,3,5-hexatrienylene, 1-propenyleneoxy, 1-methyl-1-propenyleneoxy,2-methyl-1-propenyleneoxy, 2-propenyleneoxy, 2-butenyleneoxy,1-propenyleneoxymethylene, 1-butenyleneoxy, 3-butenyleneoxy,2-pentenyleneoxy, 1-pentenyleneoxy, 3-pentenyleneoxy, 4-pentenyleneoxy,1,3-butadienyleneoxy, 1,3-pentadienyleneoxy, 2-penten-4-yleneoxy,2-hexenyleneoxy, 1-hexenyleneoxy, 5-hexenyleneoxy, 3-hexenyleneoxy,4-hexenyleneoxy, 3,3-dimethyl-1-propenyleneoxy,2-ethyl-1-propenyleneoxy, ethynyleneoxy, 2-propynyleneoxy,1-propynyleneoxy, 1,1-dimethyl-2-propynyleneoxy,3,3-dimethyl-1-propynyleneoxy, 3-butynyleneoxy, 1-butynyleneoxy,2-pentynyleneoxy, 1-pentynyleneoxy, 3-pentynyleneoxy, 4-pentynyleneoxy,2-hexynyleneoxy, 1-hexynyleneoxy, 3-hexynyleneoxy, 4-hexynyleneoxy,5-hexynyleneoxy, 1,3-hexadienyleneoxy, 1,4-hexadienyleneoxy,1,3,5-hexatrienyleneoxy, 1-propenyleneoxyethylene,1-propenyleneoxypropylene, 1-methyl-1-propenyleneoxymethylene,2-methyl-1-propenyleneoxyethylene, 2-propenyleneoxypropylene,2-butenyleneoxymethylene, 1-butenyleneoxyethylene,2-pentenyleneoxymethylene, 1,3-butadienyleneoxymethylene,1,3-pentadienyleneoxymethylene, 1-propynyleneoxymethylene,2-propynyleneoxyethylene, ethynyleneoxymethylene,3-butynyleneoxymethylene, 1-butynyleneoxyethylene,1-pentynyleneoxymethylene, 3,3-dimethyl-1-propynyleneoxymethylene,1-propenylenethio, 1-methyl-1-propenylenethio,2-methyl-1-propenylenethio, 2-propenylenethio, 2-butenylenethio,1-propenylenethiomethylene, 1-butenylenethio, 3-butenylenetio,2-pentenylenethio, 1-pentenylenethio, 3-pentylenethio,4-pentenylenethio, 1,3-butadienylenethio, 1,3-pentadienylenethio,2-penten-4-ylenethio, 2-hexenylenethio, 1-hexenylenethio,5-hexenylenethio, 3-hexenylenethio, 4-hexenylenethio,3,3-dimethyl-1-propenylenethio, 2-ethyl-1-propenylenethio,ethynylenethio, 2-propynylenethio, 1-propynylenethio,1,1-dimethyl-2-propynylenethio, 3,3-dimethyl-1-propynylenethio,3-butynylenethio, 1-butynylenethio, 2-pentynylenethio,1-pentynylenethio, 3-pentynylenethio, 4-pentynylenethio,2-hexynylenethio, 1-hexynylenethio, 3-hexynylenethio, 4-hexynylenethio,5-hexynylenethio, 1,3-hexadienylenethio, 1,4-hexadienylenethio,1,3,5-hexatrienylenethio, 1-propenylenethioethylene,1-propenylenethiopropylene, 1-methyl-1-propenylenethiomethylene,2-methyl-1-propenylenethioethylene, 2-propenylenethiopropylene,2-butenylenethiomethylene, 1-butenylenethioethylene,2-pentenylenethiomethylene, 1,3-butadienylenethiomethylene,1,3-pentadienylenethiomethylene, 1-propynylenethiomethylene,2-propynylelethioethylene, ethynylenethiomethylene,3-butynylenethiomethylene, 1-butynylenethioethylene,1-pentynylenethiomethylene, 3,3-dimethyl-1-propynylenethiomethylene,3,3-dimethyl-1-propynylenethiomethylene,N-methyl-N-(1-propenylene)amino,N-ethyl-N-(1-methyl-1-propenylene)amino,N-propyl-N-(2-methyl-1-propenylene)amino,N-n-butyl-N-(2-propenylene)amino, N-pentyl-N-(2-butenylene)amino,N-methyl-N-(1-propenylene)aminomethylene, N-hexyl-N-(1-butenylene)amino,N-methyl-N-(3-butenylene)amino, N-ethyl-N-(2-pentenylene)amino,N-propyl-N-(1-pentenylene)amino, N-tert-butyl-N-[3-pentenylene)amino,N-pentyl-N-(4-pentenylene)amino, N-hexyl-N-(1,3-butadienylene)amino,N-methyl-N-(1,3-pentadienylene)amino,N-ethyl-N-(2-penten-4-ylnylene)amino, N-propyl-N-(2-hexenylene)amino,N-n-butyl-N-(1-hexenylene)amino, N-pentyl-N-(5-hexenylene)amino,N-hexyl-N-(3-hexenylene)amino, N-methyl-N-(1-propynylene)amino,N-ethyl-N-(1,1-dimethyl-2-propynylene)amino,N-propyl-N-(3,3-dimethyl-1-propynylene)amino,N-tert-butyl-N-(3-butynylene)amino, N-pentyl-N-(1-butynylene)amino,N-hexyl-N-(2-pentynylene)amino, N-methyl-N-(1-pentynylene)amino,N-ethyl-N-(3-pentynylene)amino, N-propyl-N-(4-pentynylene)amino,N-butyl-N-(2-hexynylene)amino, N-pentyl-N-(1-hexynylene)amino,N-hexyl-N-(3-hexynylene)amino, N-methyl-N-(4-hexynylene)amino,N-ethyl-N-(5-hexynylene)amino, N-propyl-N-(1,3-hexadienylene)amino,N-tert-butyl-N-(1,4-hexadienylene)amino,N-pentyl-N-(1,3,5-hexatrienylene)amino,N-hexyl-N-(1-propenylene)aminoethylene,N-methyl-N-(1-propenylene)aminopropylene,N-ethyl-N-(1-methyl-1-propenylene)aminomethylene,N-propyl-N-(2-methyl-1-propenylene)aminoethylene,N-butyl-N-(2-propenylene)aminopropylene,N-pentyl-N-(2-butenylene)aminomethylene,N-hexyl-N-(1-butenylene)aminoethylene,N-methyl-N-(2-pentenylene)aminomethylene,N-ethyl-N-[1,3-butadienylene)aminomethylene,N-propyl-N-(1,3-pentadienylene)aminomethylene,N-methyl-N-(1-propynylene)aminomethylene,N-butyl-N-(2-propynylene)aminoethylene,N-pentyl-N-ethynyleneaminomethylene,N-hexyl-N-(3-butynylene)aminomethylene,N-methyl-N-(1-butynylene)aminoethylene,N-ethyl-N-(1-pentynylene)aminomethylene,N-methyl-N-(3,3-dimethyl-1-propynylene)aminomethylene,4-(1-propenylene)-1-piperazinyl,4-(1-methyl-1-propenylene)-1-piperazinyl,4-(2-methyl-1-propenylene)-1-piperazinyl,4-(2-propenylene)1-piperazinyl, 4-(2-butenylene)-1-piperazinyl,4-(1-propenylene)-1-piperazinylmethylene,4-(1-butenylene)-1-piperazinyl, 4-(3-butenylene)-1-piperazinyl,4-(2-pentenylene)-1-piperazinyl, 4-(1-pentenylene)-1-piperazinyl,4-(3-pentenylene)-1-piperazinyl, 4-(4-pentenylene)-1-piperazinyl,4-(1,3-butadienylene)-1-piperazinyl,4-(1,3-pentadienylene)-1-piperazinyl,4-(2-penten-4-ynylene)-1-piperazinyl, 4-(2-hexenylene)-1-piperazinyl,4-(1-hexenylene)-1-piperazinyl, 4-(5-hexenylene)-1-piperazinyl,4-(1-butynylene)-1-piperazinylethylene,4-(1-pentynylene)-1-piperazinylmethylene,4-(3,3-dimethyl-1-propynylene)-1-piperazinylmethylene,4-(3-hexenylene)-1-piperazinyl, 4-(4-hexenylene)-1-piperazinyl,4-(3,3-dimethyl-1-propenylene)-1-piperazinyl,4-(2-ethyl-1-propenylene)-1-piperazinyl, 4-(ethynylene)-1-piperazinyl,4-(2-propynylene)-1-piperazinyl, 4-(1-propynylene)-1-piperazinyl,4-(1,1-dimethyl-2-propynylene)-1-piperazinyl,4-(3,3-dimethyl-1-propynylene)-1-piperazinyl,4-(3-butynylene)-1-piperazinyl, 4-(1-butynylene)-1-piperazinyl,4-(2-pentynylene)-1-piperazinyl, 4-(1-pentynylene)-1-piperazinyl,4-(3-pentylene)-1-piperazinyl, 4-(4-pentynylene)-1-piperazinyl,4-(2-hexynylene)-1-piperazinyl, 4-(1-hexynylene)-1-piperazinyl,4-(3-hexynylene)-1-piperazinyl, 4-(4-hexynylene)-1-piperazinyl,4-(5-hexynylene)-1-piperazinyl, 4-(1,3-hexadienylene)-1-piperazinyl,4-(1,4-hexadienylene)-1-piperazinyl,4-(1,3,5-hexatrienylene)-1-piperazinyl,4-(1-propenylene)-1-piperazinylethylene,4-(1-propenylene)-1-piperazinylpropylene, 4-(1-methyl-1-propenylene)-1-piperazinylmethylene,4-(2-methyl-1-propenylene)-1-piperazinylethylene,4-(2-propenylene)-1-piperazinylpropylene,4-(2-butenylene)-1-piperazinylmethylene,4-(1-butenylene)-1-piperazinylethylene,4-(2-pentenylene)-1-piperazinylmethylene,4-(1,3-butadienylene)-1-piperazinylmethylene,4-(1,3-pentadienylene)-1-piperazinylmethylene,4-(1-propynylene)-1-piperazinylmethylene,4-(2-propynylene)-1-piperazinylethylene,4-ethylene-1-piperazinylmethylene and4-(3-butynylene)-1-piperazinylmethylene groups and others can beexemplified.

As to the tetrazolyl group which may have a lower alkyl group as thesubstituent, a tetrazolyl group which may have an alkyl group having 1to 6 carbon atom as the substituent, such as tetrazolyl,1-methyl-5-tetrazolyl, 1-ethyl-5-tetrazolyl, 1-propyl-5-tetrazolyl,1-tert-butyl-5-tetrazolyl, 1-pentyl-5-tetrazolyl, 1-hexyl-5-tetrazolyl,5-methyl-1-tetrazolyl, 5-isopropyl-1-tetrazolyl, 5-n-butyl-1-tetrazolyl,and 5-hexyl-1-tetrazolyl groups and others ca be exemplified.

As to the phenyl group which may have a hydroxyl group as thesubstituent, phenyl, 2-, 3- or 4-hydroxyphenyl group can be exemplified.

As to the straight-chain or branched-chain unsaturated hydrocarbon groupwhich may have or may not have an oxygen atom or a group of the formula##STR10## (wherein R⁷ is a lower alkyl group), a straight-chain orbranched-chain unsaturated hydrocarbon residual group having 2 to 6carbon atoms in the unsaturated hydrocarbon residual moiety, having 1 to3 double bonds and/or triple bonds therein, said unsaturated hydrocarbonresidual group may have or may not have an oxygen atom or a group of theformula ##STR11## (wherein R⁷ is an alkyl group having 1 to 6 carbonatoms), such as vinylene, 1-propenylene, 1-methyl-1-propenylene,2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene,3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene,4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene,2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene,3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene,2-ethyl-1-propenylene, ethynylene, 2-propynylene, 1-propynylene,1,1-dimethyl-2-propynylene, 3,3-dimethyl-1-propynylene, 2-butynylene,3-butynylene, -butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene,4-pentynylene, 2-hexynylene, 1-hexynylene, 3-hexynylene, 4-hexynylene,5-hexynylene, 1,3-hexadienylene, 1,4-hexadienylene,1,3,5-hexatrienylene, 1-propenyleneoxy,. 1-methyl-1-propenyleneoxy,2-methyl-1-propenyleneoxy, 2-propenyleneoxy, 2-butenyleneoxy,1-propenyleneoxy methylene, 1-butenyleneoxy, 3-butenyleneoxy,2-pentenyleneoxy, 1-pentenyleneoxy, 3-pentenyleneoxy, 4-pentenyleneoxy,1,3-butadienyleneoxy, 1,3-pentadienyleneoxy, 2-penten-4-ynyleneoxy,2-hexenyleneoxy, 1-hexenyleneoxy, 5-hexenyleneoxy, 3-hexenyleneoxy,4-hexenyleneoxy, 3,3-dimethyl-1-propenyleneoxy,2-ethyl-1-propenyleneoxy, ethynyleneoxy, 2-propynyleneoxy,1-propynyleneoxy, 1,1-dimethyl- 2-propynyleneoxy,3,3-dimethyl-1-propynyleneoxy, 3-butynyleneoxy, 1-butynyleneoxy,2-pentynyleneoxy, 1-pentynyleneoxy, 3-pentynyleneoxy, 4-pentynyleneoxy,2-hexynyleneoxy, 1-hexynyleneoxy, 3-hexynyleneoxy, 4-hexynyleneoxy,5-hexynyleneoxy, 1,3-hexadienyleneoxy, 1,4-hexadienyleneoxy,1,3,5-hexatrienyleneoxy, 1-propenyleneoxyethylene,1-propenyleneoxypropylene, 1-methyl-1-propenyleneoxymethylene,2-methyl-1-propenyleneoxyethylene, 2-propenylenexoypropylene,2-butenyleneoxymethylene, 1-butenyleneoxyethylene,2-pentenyleneoxymethylene, 1,3-butadienyleneoxymethylene,1,3-pentadienyleneoxymethylene, 1-propynyleneoxymethylene,2-propynyleneoxyethylene, ethynyleneoxymethylene,3-butynyleneoxymethylene, 1-butynyleneoxyethylene,1-pentynyleneoxymethylene, 3,3-dimethyl-1-propynyleneoxymethylene,N-methyl-N-(1-propenylene)amino,N-ethyl-N-(1-methyl-1-propenylene)amino,N-propyl-N-(2-methyl-1-propenylene)amino,N-n-butyl-N-(2-propenylene)amino, N-pentyl-N-(2-butenylene)amino,N-methyl-N-(1-propenylene)aminomethylene, N-hexyl-N-(1-butenylene)amino,N-methyl-N-(3-butenylene)amino, N-ethyl-N-[2-tentenylene)amino,N-propyl-N-(1-pentenylene)amino, N-tert-butyl-N-(3-pentenylene)amino,N-pentyl-N-(4-pentenylene)amino, N-hexyl-N-(1,3-butadienylene)amino,N-methyl-N-(1,3-pentadienylene)amino,N-ethyl-N-(2-penten-4-ynylene)amino, N-propyl-N-(2-hexenylene)amino,N-n-butyl-N-(1-hexenylene)amino., N-pentyl-N-(5-hexenylene)amino,N-hexyl-N-(3-hexenylene)amino, N-methyl-N-(1-propynylene)aminoN-ethyl-N-(1,1-dimethyl-2-propynylene)amino,N-propyl-N-(3,3-dimethyl-1-propynylene)amino,N-tert-butyl-N-(3-butynylene)amino, N-pentyl-N-(1-butynylene)amino,N-hexyl-N-(2-pentynylene)amino, N-ethyl-N-(3-pentynylene)amino,N-methyl-N-(1-pentynylene)amino, N-propyl-N-(4-pentynylene)amino,N-butyl-N-(2-hexynylene)amino, N-pentyl-N-[1-hexynylene)amino,N-hexyl-N-(3-hexynylene)amino, N-methyl-(4-hexynylene)amino,N-ethyl-N-(5-hexynylene)amino, N-propyl-N-(1,3-hexadienylene)amino,N-tert-butyl-N-(1,4-hexadienylene)amino, N-(1,3,5-hexatrienylene)amino,N-(1,3,5-hexatrienylene)amino, N-hexyl-N-(1-propenylene)aminoethylene,N-methyl-N-(1-propenylene)aminopropylene,N-ethyl-N-(1-methyl-1-propenylene)aminomethylene,N-propyl-N-(2-methyl-1-propenylene)aminoethylene,N-butyl-N-(2-propenylene)aminopropylene,N-pentyl-N-(2-butenylene)aminomethylene,N-hexyl-N-(1-butenylene)aminoethylene,N-methyl-N-(2-pentenylene)aminomethylene,N-ethyl-N-(1,3-butadienylene)aminomethylene,N-propyl-N-(1,3-pentadienylene)aminomethylene,N-methyl-N-(1-propynylene)aminomethylene,N-butyl-N-(2-propynylene)aminoethylene,N-pentyl-N-ethynyleneaminomethylene,N-hexyl-N-(3-butynylene)aminomethylene,N-methyl-N-(1-butynylene)aminoethylene,N-ethyl-N-(1-pentynylene)aminomethylene andN-methyl-N-(3,3-dimethyl-1-propynylene)aminomethylene groups and otherscan be exemplified.

Dihydropyridine derivatives and salts thereof represented by the generalformula (1) according to the present invention can be prepared byvarious methods, for examples the derivatives can be prepared by thefollowing Reaction process formula-1. ##STR12## (wherein X is a hydroxylgroup or a halogen atom; and R¹, R², R³, R⁴ and R⁵ are the same asdefined above).

In the reaction of compound (2) with compound (3), when X is a hydroxylgroup, reaction conditions usually employed in esterification reactioncan be used. The reaction may be conducted generally in the presence ofa catalyst which is usually used in esterification reactions. As to thetypical catalysts, there can be exemplified inorganic acids, such ashydrogen chloride, concentrated sulfuric acid, phosphoric acid,polyphosphoric acids, boron trifluoride and perchloric acid and others;organic acids, such as trifluoroacetic acid, trifluoromethanesulfonicacid, naphthalenesulfonic acids, p-toluenesulfonic acid, benzenesulfonicacid and ethanesulfonic acid and others; and dehydrating agents, such astrifluoromethanesulfonic acid anhydride, thionyl chloride,tetramethylureaoxalyl chloride, acetone dimethyl acetal,dicyclohexylcarbodiimide (DCC), 1-alkyl-2-halogenopyridinium halide ortosylate, N,N-carbonyldiimidazol and others can be exemplified.Additionally, acidic ion-exchange resins can also be used as thecatalysts. The amount of these catalysts is not restricted in thespecific range, and they can be used in any amount usually used incommon esterification reaction.

The reaction may be carried out in the absence or presence of a solvent.As to the solvent used in the reaction, any solvent usually used incommon esterification reaction may effectively be used. Specifically, asto the solvents, aromatic hydrocarbons, for example benzene, toluene andxylene; halogenated hydrocarbons, for example dichloromethane,dichloroethane, chloroform, carbon tetrachloride and others; ethers, forexample diethyl ether, tetrahydrofuran, dioxane, ethylene glycolmonomethyl ether, pyridine and others, and mixed solvents thereof can beexemplified.

In the above-mentioned reaction, the ratio of the amount of compound (2)to the amount of compound (3) can be selected from a wide range, and theformer is used in an equimolar quantity to 5 times the molar quantity,preferably, the equimolar quantity to 2 times the molar quantity to thelatter.

In carrying out of the above-mentioned reaction, the yield of theobjective product can be increased by removing the water formed in thereaction from the reaction system by using a dehydrating agent, such asanhydrous calcium chloride, anhydrous copper sulfate, anhydrous calciumsulfate, phosphorus pentoxide or the like. The reaction temperature ofthe reaction may be selected optionally, and there is not anyrestriction to the temperature, generally, the reaction may be carriedout in the range from about -20° to 200° C., preferably, from about 0°C. to 150° C. The reaction is completed, generally in about 10 minutesto 20 hours depend on the kind of the starting materials and thereaction condition.

In the above-mentioned reaction, when X is a halogen atom, the objectiveproduct can be obtained by carrying out the reaction under conditions ofdehydrohalogenating reaction. The dehydrohalogenating reaction iscarried out by using a basic compound as the dehydrohalogenating agent.As to the basic compound, any known. basic compound can be used, forexample inorganic basic compounds such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate, silver carbonate and others;alcoholates such as sodium methylate, sodium ethylate and others;organic basic compounds such as triethylamine, pyridine,N,N-dimethylaniline and others can be exemplified.

The dehydrohalogenating reaction can advantageously be carried out inthe presence of a solvent, and any inert solvent which does not give anyadverse effect to the reaction can be used. As to the solvents,alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycoland others; ethers, such as dimethyl ether, tetrahydrofuran, dioxane,ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, andothers; ketones such as acetone, methyl ether ketone and others;aromatic hydrocarbons, such as benzene, toluene, xylene and others;esters, such as methyl acetate, ethyl acetate and others; aprotic polarsolvents, such as N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoryl triamide and others can be exemplified. Saidreaction can also be carried out in the presence of a metal iodide, suchas sodium iodide, potassium iodide and others. The ratio of the amountof a compound (3) to the amount of a compound (2) is not specificallyrestricted and can be selected from a wide range, generally an equimolarquantity to 5 times the molar quantity, preferably an equimolar quantityto 2 times the molar quantity of the former is used to the latter. Thereaction temperature is also not specifically restricted, and generallythe reaction is carried out at a room temperature to 200° C., preferablyat from a room temperature to 160° C. The reaction is preferably carriedout in 1 to 30 hours. Thus, dihydropyridine derivatives represented bythe general formula (1) can be prepared. ##STR13## (wherein R¹, R², R³,R⁴ and R⁵ are the same as defined above).

The reaction of compound (4) with compound (5) in the above-mentionedreaction process formula-2 can also be carried out in a suitable solventin the presence or absence of a catalyst.

As to the solvent, alcohols, such as methanol, ethanol, propanol,isopropanol, butanol, ethylene glycol, and others; ethers, such astetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethyleneglycol dimethyl ether and others; aromatic hydrocarbons, such asbenzene, toluene, xylene and others; halogenated hydrocarbons, such asmethylene chloride, chloroform, 1,2-dichloromethane, and others; aproticpolar solvents, such as dimethyl sulfoxide, N,N-dimethylformamide,hexamethylphosphoryl triamide and others; carboxylic acids, such asacetic acid, propionic acid and others; and pyridine can be exemplified.

As to the catalyst used in the reaction, organic basic compounds, suchas pyridine, piperidine, triethylamine, diethylamine,1,8-diazabicyclo[5,4,0]undecene-5 (DBU) and others; metal alcoholates,such as sodium ethylate, sodium methylyate and others, inorganic basiccompounds, such as sodium hydroxide, potassium hydroxide, potassiumcarnoate, potassium acetate and others; mineral acids, such ashydrochloric acid, sulfuric acid and others; carboxylic acid, such asacetic acid, propionic acid and others, Lewis acids, such as borontrifluoride can be exemplified.

As to the ratio of the amount of compound (4) to the amount of compound(5), the latter may be used in an equimolar quantity, preferably anequimolar quantity to 2 times the molar quantity to the former. As tothe amount of the catalyst, 0.01 to 10 times the molar quantity,preferably, 0.1 to 5 times the molar quantity of the catalyst may beused to compound (4). The reaction may be carried out, generally at -20°to 200° C., preferably, -20° to 150° C., and the reaction is completedgenerally, in 10 minutes to 50 hours.

The reaction of compound (6) with compound (7) can advantageously bycarried out in the presence of a solvent. As to the solvent, any inertsolvent which does not give any adverse effect to the reaction can beused, for example, ketones, such as acetone; halogenated hydrocarbonssuch as chloroform and others; alcohols, such as methanol, ethanol,propanol, isopropanol, ethylene glycol and others; ethers, such asdiethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether,diethylene glycol dimethyl ether and others; aromatic hydrocarbons, suchas benzene, toluene, xylene and others; esters, such as methyl acetate,ethyl acetate and others; carboxylic acid, such as acetic acid,propionic acid and others; organic basic compounds such as pyridine andothers; and aprotic polar solvent such as N,N-dimethylformamide,dimethyl sulfoxide hexamethylphosphoryl triamide and others can beexemplified.

The ratio of the amount of compound (6) to the amount of compound (7)may be an equimolar quantity to 10 times the molar quantity, preferablyan equimolar quantity to 2 times the molar quantity to the former. Thereaction may generally be carried out at -20° to 200° C., preferably at50° to 150° C. The reaction is generally completed in 10 minutes to 20hours, then the desired compound represented by formula (1) can beobtained

In conducting the reaction of compound (4) with compound (5) to formcompound (6), then reacting compound (6) with compound (7) to preparethe desired compound (1), the intermediate compound (6) may not beseparated from the reaction system, thus compound (5) and compound (7)may be existed within the same reaction system and make them reacted ina simultaneous (in one step) reaction.

Among the dihydropyridine derivatives represented by the general formula(1), those having, as for the symbol R⁸, a phenyl group which containsat least one hydroxyl group as the substituent may be prepared byhydrolyzing a compound among those represented by the general formula(1) having, as for the symbol R⁸, a phenyl group which contains at leastone substituent selected from the group consisting of a lower alkoxygroup, a tetrahydropyranyloxy group, a lower alkanoyloxy group and alower alkoxy-lower alkoxy group.

The hydrolyzing reaction of the compound (1) [hereinafter referred to as"compound (1a)"] having, as for the symbol R⁸, a phenyl group whichcontains at least one substituent selected from the group consisting ofa lower alkoxy group, a tetrahydropyranyloxy group and a loweralkoxy-lower alkoxy group is carried out without in a solvent or with ina suitable solvent, by reacting an acid. As to the solvent used in thishydrolyzing reaction, water; nitrobenzene; aromatic hydrocarbons such asbenzene, toluene, xylene and others; saturated, hydrocarbons such ashexane, octane and others; lower alcohols such as methanol, ethanol,isopropanol and others; ethers such as dioxane, tetrahydrofuran andothers ketones such as acetone and others; acetic acid; acetonitrile andmixed solvents thereof can be exemplified. As to the acid used in thishydrolyzing reaction, mineral acids such as hydrochloric acid,hydrobfomic acid, sulfuric acid and others; p-toluenesulfonic acid;pyridine p-toluenesulfonate; carboxylic acids such as acetic acid,propionic acid and others; aluminium chloride; tin chloride; borontrifluoride; zinc chloride and others can be exemplified. The amount ofthe acid to be used to the amount of compound [la) may be at least anequimolar quantity, generally a large excess quantity may be used. Thereaction may be carried out generally from -30° to 200° C., preferablyfrom -30° to 100° C., and the reaction is generally completed in about0.5 to 8 hours.

The hydrolyzing reaction of the compound (1) having, as for the symbolR⁸, a phenyl group which contains at least one lower alkanoyloxy group,is carried out under reaction conditions widely employed in hydrolyzingreaction of esters. For example, the hydrolyzing reaction is carried outunder conditions of in the presence of an acid or alkali catalyst, in aninert solvent at 0° to 100° C., for 1 to 5 hours. As to the catalyst,inorganic acids such as hydrochloric acid, sulfuric acid, aluminiumchloride and others; organic acids such as acetic acid, formic acid andothers; inorganic basic compounds such as sodium hydroxide sodiumcarbonate, potassium hydroxide and others; ammonia; organic basiccompounds such as triethylamine and others can be exemplified. As to theinert solvent, water; alcohols such as methyl alcohol, ethyl alcohol andothers; carboxylic acids such as acetic acid, propionic acid and others;ethers such as diethyl ether and others; amides such asdimethylformamide, acetamide and others can be exemplified.

Among the dihydropyridine derivatives represented by the general formula(1), those having, as for the symbol R⁸, a phenyl group which containsat least one substituent selected from the group consisting of a loweralkoxy group, a tetrahydropyranyloxy group and a lower alkoxy-loweralkoxy group, can also be prepared by alkylating a compound hereinafterreferred to as "compound (1b)" having, as for the symbol R⁸, a phenylgroup which contains at least one hydroxyl group as the substituent.Said alkylating reaction is carried out under conditions usuallyemployed in common alkylating reaction. For example, alkylation iscarried out by using an alkylating agent in the presence of a basiccompound. As to the basic compound used in this reaction, alkali metalssuch as metallic sodium, metallic potassium and others; and thehydrides, hydroxides, carbonates, bicarbonates or alcoholates of thesealkali metals; aromatic amines compounds such as pyridine, piperidine,and others; organic basic compounds such as triethylamine,N,N-diethylaniline, 1,8-diazabicyclo[5,4,0]undecene-7 (DBU) and otherscan be exemplified. As to the alkylating agent, a lower alkyl halide, atetrahydropyranyl halide, dihydropyran, a lower alkoxy-lower alkylhalide, a dialkyl sulfate, a diazoalkane and others can be exemplified.

In using a lower alkyl halide, a tetrahydropyranyl halide or a loweralkoxy-lower alkoxy halide as the for alkylating agent, the alkylatingreaction is carried out effectively in a suitable solvent. As to thesolvent to be used, water; a lower alcohols such as methanol, ethanol,isopropanol, n-butanol and others; ethers such as diethyl ether,dioxane, tetrahydrofuran and others; ketones such as acetone, methylethyl ketone and others; halogenated hydrocarbons such as chloroform,dichloroethane and others; aromatic hydrocarbons such as nitrobenzene,chlorobenzene, benzene, toluene, xylene and others; aprotic polarsolvents such as N,N-dimethylformamide, dimethyl sulfoxide and otherscan be exemplified. The amount of the alkylating agent to the amount ofcompound (lb), at least an equimolar quantity, preferably an equimolarquantity to 5 times the molar quantity may be used to the latter. Thereaction is generally carried out at from -20° to 200° C., preferably at0° to 100° C., and is completed in about 10 minutes to 24 hours.

In using a dialkyl sulfate as for the alkylating agent, the alkylationreaction is carried out in an inert solvent at a room temperature to150° C. As to the dialkyl sulfate, dimethyl sulfate, diethyl sulfate andothers can be exemplified. As to the inert solvent, aromatichydrocarbons such as benzene, toluene and others; ethers such asdioxane, tetrahydrofuran, diethyl ether and others can be exemplified.

In using dihydropyran as for the alkylating agent, the alkylatingreaction is carried out in the presence of an acid, in a solvent, andgenerally at 0° to 150° C., preferably at 0° to about 100° C., and thereaction is completed in 0.5 to 10 hours. As to the acid to be used inthis case, mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and others; p-toluenesulfonic acid; pyridinep-toluenesulfonate and others can be exemplified. As to the solvent,lower alcohols such as methanol, ethanol, isopropanol and others; etherssuch as diethyl ether, dioxane, tetrahydrofuran and others; aromatichydrocarbons such as benzene, toluene and others; saturated hydrocarbonssuch as hexane, octane and others; ketones such as acetone and; aceticacid; acetonitrile and mixtures of these solvents can be exemplified.

The amount of dihydropyran to the amount of compound (1b), generally anequimolar quantity, preferably an equimolar to 5 times the molarquantity of the former may be used to the latter.

Among the dihydropyridine derivatives represented by the general formula(1), those having, as for the symbol R⁸, a phenyl group which containsat least one lower alkanoyloxy group as the substituent, can also beprepared by acylating a compound (1b). Said acylating reaction iscarried out by using an acid halide such as a lower alkanoic acidhalide, or an alkanoic acid anhydride under conventional method. Thereaction by using acid halide is carried out in a inert solvent, and ifnecessary in the presence of a dehydrohalogenating agent such as anamine for example triethylamine, diisopropylethylamine, pyridine,N,N-diethylaniline and others, and at -50° to 150° C., in 1 to 24 hours.In carrying out the acylating reaction by using acid anhydride, thereaction is conducted in an inert solvent at a room temperature to 200°C., in 1 to 10 hours. As to the inert solvent used in theabove-mentioned reaction, aromatic hydrocarbons such as nitrobenzene,chlorobenzene and others; amines such as pyridine, N,N-dimethylanilineand others; ethers such as dimethyl ether, tetrahydrofuran and others;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and others can be exemplified. The amount of the acrylatingagent used to the amount of compound (1b), generally at least anequimolar quantity, preferably an equimolar to 5 times the molarquantity of the former may be used t the latter.

Compounds represented by the general formula (3) as used for thestarting material in the above-mentioned reaction process formula-1, andcompounds represented by the general formula (4) as used for thestarting material in the above-mentioned reaction process formula-2contain novel compounds, said compounds represented by the generalformulas (3a), (3b), (3c) and (3d) are prepared by the followingreaction process formulas -3 to -5. ##STR14## [wherein R⁸ is the same asdefined above; R⁹ is a hydrogen atom or a lower alkyl group; R¹⁰ is alower alkyl group; R¹¹ is a carboxyl group or a group of the formula##STR15## (wherein R^(10') is a lower alkyl group); B and D are each anunsaturated alkylene group; m and o are 0 or 1 respectively; X¹ is ahalogen atom; provided that the carbon atom number in the group of theformula ##STR16## should not exceed 6].

The reaction of compound (8) with compound (9) can be carried out in thepresence of a basic compound, in a solvent. As to the basic compound,inorganic basis such as metallic sodium, metallic potassium, sodiumhydride, sodium amide, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate and others;metal alcoholates such as sodium methylate, sodium ethylate and others;organic basis compounds such as pyridine, piperidine, quinoline,triethylamine, N,N-dimethylaniline and others can be exemplified. As tothe solvent, any inert solvent which does not give any adverse effect tothe reaction can be used, for example, ethers such as diethyl ether,dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethyleneglycol dimethyl ether and others; aromatic hydrocarbons such as benzene,toluene, xylene and others; aliphatic hydrocarbons n-hexane, heptane,cyclohexane and others, amines such as pyridine, N,N-dimethylaniline andothers; aprotic polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), hexamethylphosphoryl triamide (HMPA) andothers can be exemplified. The reaction is generally carried out at 0°to 150° C., preferably from a room temperature to about 120° C., and isgenerally completed in 0.5 to 15 hours. The amount of compound (8) tothe amount of compound (9) is generally an equimolar quantity,preferably an equimolar quantity to 2 times the molar quantity of thelatter is used to the former.

The reduction of compound (10) is generally carried out by using ahydrogenation reducing agent. As to the hydrogenation reducing agent,sodium borohydridem lithium aluminum hydride, aluminum dialkyl hydridesuch as aluminum diisobutyl hydride (DIBAL), diborane and others. Theamount of the hydrogenation reducing agent to the amount of compound (0)is that generally 0.1 to 3 times the molar quantity, preferably 0.5 to 2times the molar quantity of the former is used to the latter. Thereaction is carried out generally in a suitable solvent, for examplewater; a lower alcohols such as methanol, ethanol, isopropanol andothers; ethers such as tetrahydrofran, diethyl ether, diethylene glycoldimethyl ether and others; aromatic hydrocarbons such as benzene,toluene, xylene and others can be used, at -60° to 50° C., preferably at-40° C. to a room temperature, for about 10 minutes to 5 hours. Incarrying out of the reaction by using lithium aluminum hydride, aluminumdialkyl hydride or diborane as for the reducing agent, an anhydroussolvent such as diethyl ether, tetrahydrofuran, diethylene glycoldimethyl ether, benzene, toluene or xylene may preferably be used.

The halogenation reaction of compound (3a) thus prepared is carried outin a solvent for example, an ether such as dioxane, tetrahydrofuran orthe like; a chlorinated hydrocarbon such as chloroform, methylenechloride, carbon tetrachloride or the like, or without a solvent, byreacting a compound [3a) with a halogenating agent for example ahydrohalic acid such as hydrochloric acid or hydrobromic acid;N,N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride,phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or thelike, at a room temperature to 150° C., preferably at a room temperatureto 80° C., for 1 to 6 hours. The amount of the halogenating agent to theamount of a compound (3a) is that at least an equimolar quantity,generally a large excess quantity of the halogenating agent may be usedto the latter. ##STR17## [wherein R⁸, B, m and X¹ are the same asdefined above; l is an integer of 3 to 6; provided that the number ofcarbon atoms in a group of the formula -(B)_(m) --CH═CH--(CH₂)_(l-1)should not be over 6].

The reaction for preparing compound (12) from compound (11) is carriedout in the presence of a basic compound, in an inert solvent forexample, an ether such as dioxane, tetrahydrofuran, ethylene glycoldimethyl ether or the like; an aromatic hydrocarbon such as benzene,toluene, xylene or the like; a lower alcohol such as methanol, ethanol,isopropanol or the like; a polar solvent such as acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide or the like. As to the basiccompound, inorganic basic compounds such as calcium carbonate, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, sodiumhydroxide, potassium hydroxide, sodium amide, sodium hydride, potassiumhydride, sodium methylate, sodium ethylate and others; and organic basiccompounds such as triethylamine, pyridine, quinoline,1,5-dibiazabicyclo[4,3,0]nonene-5 (DBN),1,8-diazabicyclo(5,4,0]undecene-7 (DBU), 1,4-diazabicyclo[2,2,2]octane(DABCO) and others can be exemplified. The reaction is generally carriedout at a room temperature to 200° C., preferably at 60° to 120° C., andthe reaction is generally completed in 1 to 24 hours.

Reduction reaction of a compound (12) is carried out under the sameconditions similar to those employed in the reduction of a compound (10)in the above-mentioned reaction process formula-3.

The reaction of a compound (13}with a compound (14) is carried out in asuitable inert solvent As to the solvent to be used in the reaction,ethers such as dioxane, tetrahydrofuran, diethyl ether and others;halogenated hydrocarbons such as chloroform, methylene chloride, carbontetrachloride and others can be exemplified. The reaction temperature isgenerally at o to 150° C., preferably at 0° to about 100° C., andgenerally, the reaction is completed in 10 minutes to 6 hours. Theamount of the compound (14) to the amount of the compound (13) is thatgenerally at least an equimolar quantity, preferably in a large excessamount of the former is used to the latter. ##STR18## [wherein R⁸, R¹⁰,B, X¹, m and o are the same as defined above; M is a metal such ascopper, sodium, lithium, potassium; D' is a saturated- orunsaturated-alkylene group; provided that the number of the carbon atomsin a group of the formula --(B)_(m) --C.tbd.C--(D')_(o) should not beexceed over 6].

The reaction of a compound (3d) with a compound (15) is carried out in asuitable solvent. As to the solvent used in the reaction, ethers such asdiethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether,diethylene glycol dimethyl ether and others; aromatic hydrocarbon suchas benzene, toluene, xylene; aliphatic hydrocarbons such as n-hexane,heptane, cyclohexane and others; amines such as triethylamine, pyridine,N,N-dimethylaniline and others; aprotic polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoryl triamide (HMPA) and others can be exemplified. Thereaction temperature is generally 0° to 200° C., preferably from a roomtemperature to at about 150° C., and the reaction is generally completedin 0.5 to 10 hours. The amount of the compound (15) to the amount of thecompound (3d) is that at least an equimolar quantity, preferably anequimolar to 1.5 times the molar quantity of the former is used to thelatter.

The reduction reaction of a compound (16) can be carried out under thesame conditions those employed in the reduction of a compound (10) inreaction process formula-3.

Compounds represented by the general formulas (3a), (3b), (3c) and (3d)can be converted into a compound represented by the general formula(17), ##STR19## [wherein Z is a group of the formula ##STR20## or--C.tbd.C--(D')_(o) --; and R⁸, R⁹, B, D, m, o and l are the same asdefined above], by oxidizing in the presence of a suitable oxidizingagent.

A part of compounds represented by the general formula (17) correspondto compound (8) which is the starting material used in theabove-mentioned reaction process formula-3, thus various desiredcompounds represented by the general formula (3) can be obtained bycarrying out the reaction in sequently in the above-mentioned reactionprocess formuls-3 to -5 and -9 and the above-mentioned oxidationreaction. As to the oxidizing agent used in the above-mentionedoxidation reaction, chromium compounds such as potassium chromate,sodium bichromate, chromium trioxide, pyridinium chlorochromate,anhydrous chromium trioxide-dipyridine complex and others; manganesecompounds such as manganese dioxide, potassium permangante and others;lead tetraacetate; periodic acid; dimethyl sulfoxide; amine oxides suchas dimethylamine oxide; pyridine-nitroso compounds such apyridine-p-nitro-N,N-dimethylaniline and others can be exemplified. Asto the solvent used to the reaction, aromatic hydrocarbons such asbenzene, toluene, xylene and others; halogenated hydrocarbons such asmethylene chloride, chloroform, carbon tetrachloride and others; etherssuch as diethyl ether, dioxane, tetrahydrofuran and others, aliphatichydrocarbons such as haxane, pentane, cyclohexane and others, ketonessuch as acetone, methyl ethyl keton and others; lower alcohols such asmethanol, ethanol, isopropanol; water, acetic acid, dimethyl sulfoxideand others can be exemplified. The reaction can be carried out by usingan acid such as sulfuric acid or perchloric acid as the catalyst. Thereaction is carried out generally at 0° to 200° C., preferably at 0° toabout 150° C., is completed generally in 0.5 to 15 hours.

A compound represented by the general formula (11) a used for thestarting material in the above-mentioned reaction is prepared by forexample the following reaction process formula-7. ##STR21## [wherein R⁸,B, m, l and X¹ are the same as defined above].

The reaction of a compound (18) with a compound (19) is carried out in asuitable solvent. As to the solvent used in the reaction, ethers such asdiethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and others;aromatic hydrocarbons such as benzene, toluene, xylene and others;aliphatic hydrocarbons such as hexane, heptane, pentane and others; andmixtures of these solvents and others can be exemplified

The reaction is carried out generally at -70° to 50° C., preferably -65°C. to about a room temperature, and is generally completed in 3 to 30hours. The amount of the compound (19) to the amount of the compound(18) is that at least 2 times the molar quantity, preferably 2 to 3times the molar quantity of the former is used to the latter.

Among the compounds represented by the general formula (11), those inwhich the symbol m is 0 thus compound (11a) may be prepared by thefollowing reaction process formula-8. ##STR22## (wherein R⁸, X¹ and lare the same as defined above; and X² is a halogen atom).

The reaction of a compound (20) with a compound (21) o compound (22) isgenerally called as Friedel-Crafts reaction, and can be carried out in asuitable solvent in the presence of a Lewis acid. As to the solvent usedin the reaction, any solvent generally used in this type of reaction canadvantageously be employed, for example carbon disulfide, nitrobenzene,chlorobenzene, dichloroethane, dichloromethane, trichloroethane,tetrachloroethane and others can be exemplified. As to the Lewis acidused in this reaction, those used conventionally in this type ofreaction can preferably be used, for example aluminum chloride, zincchloride, iron chloride, tin chloride, boron trifluoride, borontribromide, concentrated sulfuric acid and others can be used. Theamount of Lewis acid may be determined suitably, and generally 2 to 6times the molar quantity, preferably 3 to 4 times the molar quantity ofa Lewis acid may be used to a compound (20). The amount of the compound(21) or compound (22) to the amount of the compound (20) is thatgenerally at least an equimolar quantity, preferably an equimolarquantity to 3 times the molar quantity of the former is used to thelatter. The reaction temperature can be selected from a wide range, andgenerally the reaction is carried out at 0° to 120° C., preferably from0° to 70° C., and the reaction is completed in 0.5 to about 6 hours.##STR23## [wherein R⁸, B, D', m and o are the same as defined above; R¹²is a hydroxyl group or a lower alkanoyl group; provided that the numberof the carbon atoms in a group of the formula --(B)_(m)--C.tbd.C--(D')_(o) --CH₂ -- and a group of the formula --(B)_(m)--CH.tbd.CH--(D')_(o) --CH₂ -- should not exceed over 6.].

The reduction of a compound (3f) can be carried out by methods accordingt various reducing reactions known in the art. For example, catalyticreducing method by using palladium black, palladium carbon, platinumoxide, platinum black, Raney nickel, Lindlar catalyst and others as forthe reducing catalysts; reducing methods by using sodium borohydride,lithium aluminum hydride and others as for the reducing agents can beemployed.

In carrying out the catalytic reduction, the reaction can be conductedby using a conventional solvent for example water, methanol, ethanol,isopropanol, acetic acid, dioxane, tetrahydrofuran and others, and inthe presence of the above-mentioned catalyst, under a normal atmosphericpressure to 20 atmospheric pressure, preferably, from a normalatmospheric pressure to 10 atmospheric pressure of hydrogen, andgenerally at -30° C. to 100° C., preferably 0° C. to 50° C. The amountof the catalyst is generally 0.1 to 40% by weight, preferably from 1 to20% by weight of the catalyst is used to a compound (3f), and thereaction is generally completed in 1 to 12 hours.

In carrying out the reaction by using a reducing agent such as lithiumaluminum hydride, an equimolar quantity to 20 times the molar quantity,preferably 1.5 to 3.5 times the molar quantity of the reducing agent isused to the compound (2f). The reduction reaction is carried out in aconventional solvent such as diethyl ether, tetrahydrofuran, dioxane orthe like, and generally at -30° to 100° C., preferably at 0° C. to 70°C., and is completed in 30 minutes to about 12 hours. According to theseprocedures, a compound represented by the general formula (3g) caneasily be obtained.

Among the compounds represented by the general formula (3g), thosehaving a lower alkanoyloxy group as for the symbol R¹², can be convertedinto a compound (3g) having a hydroxy group as for the symbol R¹² underthe conditions similar to those employed in the hydrolysis of a compound(1) wherein R⁸ is a phenyl group which contains at least one loweralkanoyloxy group as the substituent.

A part of compounds represented by the general formula (3f) can beprepared by a method according to the following reaction processformula-10. ##STR24## [wherein R⁸, B, m, X¹, M, D' and o are the same asdefined above; R¹³ is a hydroxyl group, tetrahydropyranyloxy group, alower alkoxy-lower alkoxy group or a lower alkanoyl group; provided thatthe number of the carbon atoms in a group of the formula --(B)_(m)--C.tbd.C--(D')_(o) --CH₂ -- should not exceed over 6].

The reaction of a compound (3d) with a compound (23) can be carried outunder the same reaction conditions employed in the reaction of acompound (3d) with a compound (15) in the above-mentioned reactionprocess formula-5. ##STR25## wherein ⁸, B, and m are the same as definedabove].

The reduction reaction of a compound (8a) can be carried out under thesame reaction conditions employed in the reduction of a compound (10) inthe above-mentioned reaction process formula-3. ##STR26## [wherein R⁸,D, D' and o are the same as defined above; Y is an oxygen atom, a sulfuratom, a group of the formula ##STR27## or a group of the formula##STR28## (wherein R⁷ is the same as defined above); provided that thenumber of the carbon atoms in a group of the formula --(D)_(o) --CH₂--Y--(D)'_(o) --CH₂ -- should not be exceeded over 6].

The reaction of a compound (24) with a compound (25) can be carried outin a suitable solvent or without solvent, in the absence or presence ofa basic compound. As to the solvent used in the reaction, water; loweralcohols such as methanol, ethanol, isopropanol and others; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform, carbontetrachloride and others; ethers such as diethyl ether, tetrahydrofuran,dioxane and others; aliphatic hydrocarbons such as n-hexane, octane,cyclohexane and others; aromatic hydrocarbons such as benzene, toluene,xylene and others; aprotic polar solvents such as acetone, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoryl triamideand others; and mixtures of these solvents can be exemplified. As to thesolvent used in the reaction, inorganic basic compounds such as sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydrogen carbonate, potassium hydrogen carbonate, sodium amide,sodium hydride and others; alcoholates such as sodium methylate, sodiumethylate and others; organic basic compounds such as triethylamine,pyridine, N,N-dimethylaniline and others can be exemplified.

The said reaction can be advantageously proceed by using acharge-transfer catalyst such as tetrabutylammonium bromide and others.The reaction is carried out generally, at 0° to 150° C., preferably at0° to 120° C., and is completed in about 1 to 10 hours. The ratio of theamount of a compound (24) to the amount of a compound (25) is thatgenerally an equimolar quantity, preferably an equimolar quantity to 10times the molar quantity of the former is used to the latter.

A compound (4) used as the starting material in the reaction processformula-2 can be prepared by methods according to reaction processformula-13 and -14 as follows. ##STR29## [wherein R⁵ is the same asdefined above].

The reaction of a compound (26) with a compound (27) in theabove-mentioned reaction process formula-13 is carried out in a suitablesolvent in the presence of a catalyst. As to the catalyst, basiccompounds for example, organic basic compounds such as triethylamine,pyridine, N,N-dimethylaniline and others; inorganic basic compounds suchas sodium acetate, potassium carbonate; and acidic compounds forexample, sulfonic acids such a p-toluenesulfonic acid and others; Lewisacids such as boron trifluoride and others ca be exemplified. As to thesolvents, aromatic hydrocarbons such as benzene, toluene, xylene andothers; esters such as methyl acetate, ethyl acetate and others;halogenated hydrocarbons such as methylene chloride, chloroform,1,2-dichloroethane and others; ethers such as diethyl ether,tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dithyleneglycol dimethyl ether and others; ketones such as acetone, methyl ethyleketone and others; aprotic polar solvents such as N,N-methylformamide,dimethyl sulfoxide, hexamethylphosphoryl trimaide, N-methylpyrrolidoneand others can be exemplified. As to the ratio of the amount of thecompound (26) to the amount of the compound (27), generally at least anequimolar quantity, preferably an equimolar quantity to 2 times themolar quantity of the latter may be used to the former. The amount ofthe catalyst is not specifically restricted, and generally 0.01 to 10times the molar quantity, preferably 0.1 to 5 times the molar quantityof the catalyst may be used to the compound (26). The reaction iscarried out generally at -20° to 200° C., preferably at -20° to 100° C.,and is completed in 10 minutes to 20 hours. ##STR30## [wherein R⁵ is thesame as defined above; and R^(2') is a lower alkyl group].

The reaction of a compound (26) with a known compound (28) may becarried out under the same conditions employed in the reaction of acompound (26) with a compound (27) in the above-mentioned reactionprocess formula-13. ##STR31## [wherein R⁵, X¹, M, A and R⁶ are the sameas defined above].

The halogenation reaction of a compound (4c) can be carried out in asuitable solvent, in the presence of a halogenating agent. As to thesolvent used in the halogenation reaction, halogenated hydrocarbons suchas chloroform, dichloromethane, carbon tetrachloride and others; etherssuch as diethyl ether, tetrahydrofuran, dioxane and others; and aceticacid can be exemplified. As to the halogenating agent used in thishalogenation reaction, halogen molecules such as bromine, chlorine andothers; metal halides such as cupric bromide, cupric chloride, lithiumchloride and others; thionyl chloride; N-halogenated succinimides suchas N-chlorosuccinimide, N-bromosuccinimide and others can beexemplified.

The halogenating agent may generally be used in a large excess amount.The halogenation is carried out generally at 0° to 150° C., preferablyat 0° to 120° C., and is completed in.1 to 24 hours.

The reaction of a compound (29) with a compound (30) can h=carried outin a suitable solvent, in the presence of a basic compound. As to thesolvent used in this reaction, ethers such as diethyl ether, dioxane,tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycoldimethyl ether and others; aromatic hydrocarbons such as benzene,toluene, xylene and others; aliphatic hydrocarbons such as n-hexane,heptane, cyclohexane and others; aprotic polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoryl triamideand others can be exemplified. As to the basic compounds, inorganicbasic compounds such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, metallic sodium, metallic potassium, sodium amide,sodium hydride and others; alcoholates such as sodium methylate, sodiumethylate and otherss; organic basic compounds such as triethylamine,pyridine, N,N-dimethylaniline and others can be exemplified.

The reaction is generally carried out at a room temperature to 200° C.,preferably at a room temperature to 150° C., and is completed in 1 to 24hours. The ratio of the amount of the compound (30) to the amount of thecompound (29) is generally at least an equimolar quantity, preferably anequimolar quantity to 2 times the molar quantity of the former is usedto the latter.

Dihydropyridine derivatives represented by the general formula (1) canalso be prepared by the methods as shown in the following reactionprocess formula-16 and -18. ##STR32## [wherein R¹, R², R³, R⁴ and X¹ arethe same as defined above; E is a lower alkylene group; R is a1,2,3,6-tetrahydropyridyl group which may have, as the substituent, aphenyl group which may have halogen atoms or lower alkyl groups as thesubstituents on the phenyl ring, group of the formula R⁶ --(D')_(o)--Y-- (wherein R⁶, D', Y and o are the same as defined above)].

The reaction of a compound (31) with a compound (32) may be carried outin a suitable solvent, in the absence or presence of a basic compound.As to the solvent used in the reaction, halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride, andothers; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethyleneglycol dimethyl ether and others; aliphatic hydrocarbons such asn-hexane, octane, cyclohexane and others; aromatic hydrocarbons such asbenzene, toluene, xylene and others; aprotic polar solvents such asacetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoryl triamide and others can be exemplified. As to thebasic compounds used in the reaction, inorganic basic compounds such assodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, sodium hydride and others; aminessuch as triethylamine, diisopropylethylamine, pyridine, quinoline andothers can be exemplified. Further, the reaction can be carried out, ifnecessary, by adding an alkali metal iodied such as potassium iodied,sodium iodide or the like, or hexamethylphosphoryl triamide as thereaction accelarator. The reaction is carried out at a room temperatureto 200° C., preferably at a room temperature to 120° C., and iscompleted in 1 to 24 hours.

The ratio of the amount of the compound (32) to the amount of thecompound (31) is at least an equimolar quantity, preferably an equimolarquantity to 5 times the molar quantity of the former to the latter.

Among the compounds represented by the general formula (32), some ofthem are novel compounds and they can prepared by a method for exampleaccording to the following reaction process formula-17. ##STR33##[wherein R⁸, D', o and X¹ are the same as defined above; and R¹⁵ is alower alkanoyl group].

The reaction of a compound (33) with a compound (34) can be carried outunder the same condition employed in the reaction of a compound (24)with a compound (25), and the hydrolysis followed by the reaction can becarried out under the same conditions employed in the hydrolysis of acompound (3 g) in the above-mentioned reaction process formula-9.##STR34## [wherein R¹, R², R³, R⁴, E, X¹, R⁸, D' and o are the same asdefined above; and X² is a halogen atom].

The reaction of a compound (31) with piperazine can be carried out underthe same conditions employed in the reaction of a compound (31) with acompound (32). Further, the reaction of a compound (36) with a compound(34a) can be carried out under the same conditions employed in thereaction of a compound [24) with a compound (25).

Among the compounds represented by the general formula (1), those havingbasic groups can be converted into the corresponding salts by treatingwith pharmacologically acceptable acids. Examples of such acidsincluding inorganic acids such as sulfuric acid, nitric acid,hydrochloric acid, hydrobromic acid and others; as well as organic acidssuch as oxalic acid, maleic acid, fumaric acid, malic acid, citric acid,benzoic acid and others.

Compound of the present invention thus prepared can easily be isolatedand purified by a method usually employed in separation, such asprecipitation, extraction, recrystallization, column chromatography,preparative thin layer chromatography and others.

Compound of the present invention represented by the general formula (1)contains inevitably its singly or together with conventionalpharmacologically acceptable carriers, to animals as well as to humanbeings. No particular restriction is made to the administration unitforms, thus compound of the present invention represented by the generalformula (1) can be used in any desired administration unit form.Suitable administration unit forms including peroral administration unitforms such as tablets, granules and solutions; and parenteraladministration unit forms such as injections.

Dosage of a compound represented by the general formula (1) as theactive ingredient to be administered is not subjected to any particularrestriction and can be selected from a wide range. For the purpose ofattaining the desired pharmacological effects, it is recommended toselect a dosage from the range of 0.06 to 10 mg/kg of the bodyweight/day. It is suggested also to contain 1 to 500 mg of the activeingredient in each of the desired administration unit form.

In the present invention, the desired peroral administration unit formssuch as tablets, capsules and solutions can be prepared by conventionalmethods. For the purpose of shaping the administration unit form intothe form of tablets, a compound of the present invention is mixed withpharmaceutically acceptable excipients such as gelatin, starch, lactose,magnesium stearate, talcum powder and gum arabic and others. Capsulescan be prepared by mixing a compound of the present invention with aninert pharmaceutically acceptable fillers or diluents and filling themixture obtained into rigid gelatin capsules or soft capsules. Sirups orelixiers may be prepared by mixing a compound of the present inventionwith a sweetening agent such as sucrose; anticeptice such as methyl- orpropyl-parabens; colorants; seasoning agents and/or other suitableadditives. Parenteral preparations can also be prepared by conventionalmethods, thus a compound of the present invention is dissolved in asterilized liquid vehicle. As to the preferable vehicle, water or salinecan be used. Liquid preparations having desired transparency, stabilityand parenteral use adaptability can be prepared by dissolvingapproximately 1 to 500 mg of the active ingredient in a solution ofpolyethylene glycol having the molecular weight of 200 to 5,000, whichis soluble in both water and organic solvents. Desirably, such liquidpreparations may contain a lubricant such as sodium carboxymethylcellulose, methyl cellulose, polyvinyl pyrrolidone and polyvinylalcohol. Said liquid preparations may also contain a bactericide andfungicide such as benzyl alcohol, phenol and thimerosal, and ifnecessary, an isotonic agent such as sucrose or sodium chloride, a localanesthetic, stabilizer and buffer solutions. Furthermore, additionalensurance of stability, the parenteral compositions may be freezed afterfilling and dehydrating steps by known lyophilization techniques. Thelyophilized powder of the parenteral composition can be made again intoa normal use from just before the use.

PREPARATION OF TABLETS

1,000 Tablets for peroral use, each containing mg of methyl3-(4-hydroxyphenyl)-2-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate areprepared from the following formulation.

    ______________________________________                                        Formulation            Amount (g)                                             ______________________________________                                        Methyl 3-(4-hydroxyphenyl)-2-                                                                        5                                                      propenyl 1,4-dihydro-2,6-dimethyl-                                            4-(3-nitrophenyl)pyridine-3,5-                                                dicarboxylate                                                                 Lactose (Japanese Pharmacopoeia                                                                      50                                                     official drug grade)                                                          Corn starch (Japanese Pharmacopoeia                                                                  25                                                     official drug grade)                                                          Crystalline cellulose (Japanese                                                                      25                                                     Pharmacopoeia official drug grade)                                            Methyl cellulose (Japanese                                                                           1.5                                                    Pharmacopoeia official drug grade)                                            Magnesium stearate (Japanese                                                                         1                                                      Pharmacopoeia official drug grade)                                            ______________________________________                                    

Methyl 3-(4-hydroxyphenyl)-2-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate,lactose, corn starch and crystalline cellulose are mixed well, and themixture is granulated with 5%-methyl cellulose aqueous solution, thenthe granules are passed through a 200 mesh sieve and then driedcarefully. The dried granules are passed through a 200 mesh sieve andmixed with magnesium stearate, then pressed into the form of tablets.

PREPARATION OF CAPSULES

1,000 Capsules of two-piece rigid gelatin capsules for peroral use, eachcontaining 10 mg of methyl 3 (4-hydroxyphenyl)-2-propynyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate areprepared by using the following formulation.

    ______________________________________                                        Formulation             Amount (g)                                            ______________________________________                                        Methyl 3-(4-hydroxyphenyl)-2-                                                                         10                                                    propynyl 1,4-dihydro-2,6-dimethyl-                                            4-(3-nitrophenyl)pyridine-3,5-                                                dicarboxylate                                                                 Lactose (Japanese Pharmacopoeia                                                                       80                                                    official drug grade)                                                          Starch (Japanese Pharmacopoeia                                                                        30                                                    official drug grade)                                                          Talcum powder (Japanese Pharmacopoeia                                                                  5                                                    official drug grade)                                                          Magnesium stearate (Japanese                                                                           1                                                    Pharmacopoeia official drug grade)                                            ______________________________________                                    

The above-mentioned ingredients are finely ground, then mixedsufficiently to a uniform mixture and filled into gelatin capsules of asize having desired size for peroral administration.

PREPARATION OF INJECTION SOLUTION

A sterile aqueous solution suitable for parenteral use is prepared fromthe following formulation.

    ______________________________________                                        Formulation               Amount (g)                                          ______________________________________                                        Methyl 3-(4-hydroxyphenyl)-2-                                                                           1                                                   propenyl 1,4-dihydro-2,6-dimethyl-                                            4-(3-nitrophenyl)pyridine-3,5-                                                dicarboxylate                                                                 Polyethylene glycol (M. W. = 4,000)                                                                     0.9                                                 (Japanese Pharmacopoeia official                                              drug grade)                                                                   Sodium chloride (Japanese Pharmacopoeia                                                                 0.9                                                 official drug grade)                                                          Polyoxyethylene sorbitan monooleate                                                                     0.4                                                 (Japanese Pharmacopoeia official                                              drug grade)                                                                   Sodium metabisulfite      0.1                                                 Methyl p-hydroxybenzoate (Japanese                                                                      0.18                                                Pharmacopoeia official drug grade)                                            Propyl p-hydroxybenzoate (Japanese                                                                      0.02                                                Pharmacopoeia official drug grade)                                            Distilled water for injection                                                                           100    (ml)                                         ______________________________________                                    

The above-mentioned methyl p-hyroxybenzoate, propyl p-hydroxybenzoate,sodium metabisulfite and sodium chloride are dissolved in about a halfvolume of distilled water at 80° C. under stirring condition. Thesolution obtained is cooled to 40° C., then methyl3-(4-hydroxyphenyl)-2-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate,polyethylene glycol and polyoxyethylene sorbitan monooleate aredissolved in the solution. Thus obtained solution is further mixed withthe distilled water for injection so as to make it into the finalvolume, then sterilized by sterile filtration with a suitable filterpaper.

The present invention will be illustrated more specifically by way ofthe following examples, in which the preparations of the compounds to beused for the starting materials will be shown in Reference Examples andthe preparations of the objective compounds will be shown in Examples.The present invention, however will not restricted to these examples.

REFERENCE EXAMPLE 1

To 20 g of p-hydroxybenzaldehyde and 32.5 g of monoethyl malonate wereadded 6 ml of pyridine and 0.2 ml of piperidine, then the mixture thusobtained was heated at 100° to 110° C. for 10 hours under stirring. Thereaction mixture was then cooled, extracted with chloroform, and thechloroform layer was washed with a saturated aqueous solution ofpotassium hydrogen sulfite and water in this order, the chloroformextract was dried with magnesium sulfate. The solvent was removed byevaporation and the residue thus obtained was crystallized fromisopropyl ether-n-hexane to yield 25.2 g of ethyl 4-hydroxycinnamate.Light yellow indefinite form crystals. Melting point: 70°-71° C.

REFERENCE EXAMPLE 2

By using 20 g of 3 hydroxybenzaldehyde and 32.5 g of monoethyl malonateas the starting materials, and by a method similar to that described inReference Example 1, under reaction conditions similar thereto, therewas prepared 25.5 g of ethyl 3-hydroxycinnamate Melting point: 65°-68°C. (from isopropyl ether)

REFERENCE EXAMPLE 3

By using 25.8 g of 4-hydroxy-3-chlorobenzaldehyde and 32.5 g ofmonoethyl malonate as the starting materials, and by a method similar tothat described in Reference Example 1, under reaction conditions similarthereto, there was prepared 46 g of ethyl 4-hydroxy-3-chlorocinnamate.Colorless prism-like crystals (from methylene chloride). Melting point:118°-119° C.

REFERENCE EXAMPLE 4

To 30 ml of anhydrous ether solution containing 5 g of ethyl4-hydroxycinnamate was added 7.1 ml of dihydropyran and 50 mg ofp-toluenesulfonic acid were added, the mixture was stirred at a roomtemperature for 2 hours, the reaction mixture was neutralized with1%-sodium hydroxide solution, washed with water, and dried withanhydrous sodium sulfate. The solvent was removed by evaporation toyield 6.8 of ethyl 4-(2-tetrahydropyranyloxy)cinnamate. Colorlessindefinite form crystals. Melting point: 52°-53° C.

REFERENCE EXAMPLE 5

50 Milliliters of anhydrous ether solution containing 6.8 g of ethyl4-(2-tetrahydropyranyloxy)cinnamate was added dropwise to an anhydrousether solution containing 0.47 g of lithium aluminium hydride beingcooled at -30° C. After the addition was finished, the reaction mixturewas stirred for 1 hour at the same temperature, then the temperature ofthe reaction mixture was gradually elevated up to -10° C., then asaturated aqueous solution of sodium sulfate was gradually added to thereaction mixture, and the precipitates formed were removed byfiltration. The filtrate was dried with anhydrous sodium sulfate, thenconcentrated to dryness, the residue thus obtained was treated by meansof silica gel column chromatography (eluent:chloroform) to yield 3.2 gof 4-(2-tetrahydropyranyloxy)cinnamyl alcohol in the form of colorlessoily substance. Refractive index: n_(D) ²² 1.5520.

REFERENCE EXAMPLE 6

15 Gram of 4-(2-tetrahydropyranyloxy)cinnamyl alcohol and 5.2 g ofsodium acetate were suspended in anhydrous methylene chloride, then tothis suspension was added in one time 18 g of pyridium chlorochromateunder ice-cooled condition. The reaction mixture was stirred for 1 hourat the same temperature, then the temperature was elevated to a roomtemperature, and the reaction mixture was stirred for additional 1 hour.100 Milliliters of ether was added to the reaction mixture, the wholemixture was filtered with Celite (a trademark for diatomaceous productmanufactured by and sold from Johns-Manville Products Corp., CeliteDivision, New York, N.Y., U.S.A.), the filtrate was concentrated and theresidue thus obtained was treated by silica gel column chromatography.Recrystallization from ether to yield 3.5 g of4-(2-tetrahydropyranyloxy)cinnamyl aldehyde in the form of colorlessneedle-like crystals. Melting point: 65°-67° C.

REFERENCE EXAMPLE 7

5.6 Grams of triethyl phosphonoacetate was added dropwise under stirringcondition at a room temperature to a tetrahydrofuran solution containing1.06 g of 60%-sodium hydride, then the reaction mixture was furtherstirred at 40° C. for 1 hour. The reaction mixture was cooled to a roomtemperature, then a tetrahydrofuran solution containing 5.6 g of4-(2-tetrahydropyranyloxy)cinnamyl aldehyde was added thereto, andstirred at a room temperature for 2 hours, then the reaction mixture waspoured into 100 ml of water. The whole mixture was extracted with ether,and the ether layer was washed with water, and a saturated aqueoussolution of sodium chloride in this order, then dried with anhydroussodium sulfate. Recrystallization from isopropyl ether to yield 3.8 g ofethyl 5-[4-(2-tetrahydropyranyloxy)phenyl]-2(E),4(E)-pentadienoate inthe form of colorless needle-like crystals. Melting point: 66°-67.5°.

REFERENCE EXAMPLE 8

To 30 ml of anhydrous benzene solution containing 3.6 g of ethyl5-(4-(2-tetrahydropyranyloxy)phenyl]-2(E),4(E)-pentadienoate was addeddropwise 15 ml of diisobutyl aluminium hydride (25% by weight/by volume)under water-cooled condition and the reaction mixture was stirred at aroom temperature for 2 hours. The reaction mixture was then poured intoa saturated aqueous solution of ammonium chloride and stirred at a roomtemperature for 2 hours. The insoluble matters were treated with Celite,and the insoluble matters were washed with ether. The organic layer waswashed with water and dried with anhydrous sodium sulfate, thenconcentrated to obtain the residue. The residue was recrystallized fromchloroform-n-hexane to yield 2.8 g of5-[4-(2-tetrahydropyranyloxy)phenyl]-2(E),4(E)pentadienolate was addeddropwise 15 ml of in the form of colorless needle-like crystals. Meltingpoint: 54°-58° C.

REFERENCE EXAMPLE 9

25 Grams of p-hydroxyacetophenone, 50 ml of dihydropyrane and 0.25 g ofp-toluenesulfonic acid were stirred at a room temperature for 2 hours inanhydrous ether. Then the reaction mixture was neutralized with1N-sodium hydroxide and washed with water and a saturated sodiumchloride aqueous solution in this order, then dried with anhydroussodium sulfate. The product was concentrated to yield 34 g of4-(2-tetrahydropyranyloxy)acetophenone. Colorless prism-like crystals.Melting point: 79°-83° C.

REFERENCE EXAMPLE 10

45.8 Grams of triethyl phosphonoacetate and an anhydrous tetrahydrofuransolution containing 8.7 g of 60%-sodium hydride were stirred at 40° C.for 1 hour, the reaction mixture was cooled and 30 g of4-(2-tetrahydropyranyloxy)acetophenone was added to the reactionmixture. The whole reaction mixture was refluxed for 4 hours by heating,then the solvent was removed by evaporation, the residue thus obtainedwas extracted with ether and washed with water, than dried. The extractwas concentrated and the residue thus obtained was treated by means ofsilica gel column chromatography to yield 27.5 g of ethyl3-methyl-p-(2-tetrahydropyranyloxy)cinnamate in the form of light yellowoily substance.

¹ H-NMR (90 MHz, CDCl₃) δ: 1.29 (3H, t, J=6Hz), 1.4-2.1 (6H, m), 2.49(3H, d, J=1Hz), 3.3-3.9 (2H, m), 4.10 (2H, q, J=6Hz), 5.3-5.45 (1H, m),6.03 (1H, d, J=1Hz), 6.9-7.4 (4H, m)

REFERENCE EXAMPLE 11

To a tetrahydrohydrofuran solution containing 27.5 g of ethyl3-methyl-p-(2-tetrahydropyranyloxy)cinnamate was added dropwise 118 mlof diisobutyl aluminium hydride (25% by weight/volume) at a roomtemperature. After 2 hours, the reaction mixture was poured into anice-cooled ammonium chloride aqueous solution, and the insoluble matterswere removed by filtration. The filtrate was washed with water thendried with anhydrous sodium sulfate and concentrated. The residue thusobtained was purified by means of silica gel column chromatography toyield 12.7 g of 3-methyl-p-(2-tetrahydropyranyloxy)cinnamyl alcohol inthe form of colorless oily substance.

¹ H-NMR (90 MHz, CDCl₃) δ: 1.5-2.0 (6H, m), 2.0 (3H, s), 3.3-4.0 (2H,m), 4.1-4.3 (3H, m), 5.26-5.4 (1H, m), 5.81 (1H, t, J=6Hz), 6.8-7.5 (4H,m).

REFERENCE EXAMPLE 12

To a carbon disulfide solution containing 53 g of aluminium chloride and26.2 g of thioanisol was added dropwise under an ice-cooled condition24.0 ml of γ-chlorobutyryl chloride. After 1 hour and 30 minutes, thereaction mixture was poured into ice-water and the insoluble matterswere collected by filtration, dissolved in chloroform. The chloroformsolution was washed with water and dried with anhydrous sodium sulfate,and concentrated to dryness. Recrystallization from methanol to yield36.2 g of γ-chloro-4-methylthiobutyrophenone in the form of light yellowprism-like crystals. Melting point: 75°-76° C.

REFERENCE EXAMPLE 13

35 Grams of δ-chloro-4-methylthiobutyrophenone, 34 ml of1,8-diazabicyclo[5,4,0]undecene-7 (DBU) and 150 ml of acetonitrile wererefluxed for 4 hours, then 500 ml of water was added to the reactionmixture, and the whole mixture was extracted with ether. The etherextract was washed with water, dried and the solvent was removed byevapolation. The residue thus obtained was recrystallized from methanolto yield 24.6 g of cyclopropyl (4-methylthiophenyl)ketone as in the formof light yellow prism-like crystals. Melting point: 76°-76.5° C.

REFERENCE EXAMPLE 14

To 200 ml of methanol solution containing 24 g of cyclopropyl(4-methylthiophenyl)ketone was added slowly 9.4 g of sodium borohydrideunder an ice-cooled condition, the reaction mixture was stirred for 2hours. Then an adequate amount of acetone was added to the reactionmixture and concentrated under a reduced pressure. To the residue thusobtained was added chloroform, and the chloroform solution was washedwith water, dried with anhydrous sodium sulfate, and the solvent wasremoved by evaporation to yield 18 g of 1-(cyclopropyl,hydroxylmethyl)-4-methylthiobenzene as in the form of colorless oilysubstance.

NMR (90 MHz, CDCl₃) δ: 0.2-0.7 (4H, m), 0.9-1.4 (1H, m), 1.4-2.0 (6H,m), 3.2-3.7 (2H, m), 5.17-5.3 (1H, m), 6.8-7.3 (8H, m).

REFERENCE EXAMPLE 15

To 10 ml of dioxane solution containing 5 g of 1-(cyclopropyl,hydroxymethyl)-4-methylthiobenzene was added dropwise 6 ml of 47% ofhydrobromic acid under an ice-cooled condition, then the mixture wasstirred for 30 minutes, and the reaction mixture was concentrated undera reduced pressure. To the residue thus obtained was added water, thenextracted with ether, the extract was washed with water and dried withanhydrous sodium sulfate, and concentrated to dryness. The residue wasrecrystallized from methanol to yield 2.2 g of4-(4'-methylthiophenyl)-3(E)-butenylbromide in the form of colorlessflake-like crystals. Melting point: 54°-56° C.

REFERENCE EXAMPLE 16

10 Grams of p-iodophenol, 8 ml of dihydropyrane and a catalytic amountof p-toluenesulfonic acid was dissolved in 30 ml of anhydrous ether, allof these were mixed together and stirred at a room temperature for 2hours. The reaction mixture was washed with water, dried then thesolvent was removed by evaporation to yield 12.4 g of4-(2-tetrahydropyranyloxy)-1-iodobenzene in the form of yellow oilysubstance. Boiling point: 84°-87° C. (at 25 mm Hg).

REFERENCE EXAMPLE 17

6.25 Grams of triethyl phosphonocrotonate was added dropwise to atetrahydrofuran solution containing 1.06 g of 60%-sodium hydride at aroom temperature, the reaction mixture was stirred for 1 hour at 40° C.The temperature of the reaction mixture was cooled to a roomtemperature, then a tetrahydrofuran solution containing 5.0 g ofp-(2-tetrahydropyranyloxy)benzaldehyde was added to the reactionmixture, and stirred at a room temperature for 2 hours, then poured into100 ml of water. The whole mixture was extracted with ether, the etherextract was washed with water and a saturated sodium chloride aqueoussolution in this order, then dried with anhydrous sodium sulfate. Thesolvent was removed by evaporation, the residue thus obtained waspurified by means of silica gel column chromatography (eluent:hexane-chloroform), next recrystallized from isopropyl ether to yield4.01 g of ethyl5-[4-(2-tetrahydropyranyloxyphenyl)]-2[E),4(E)-pentadienoate. Colorlessneedle-like crystals. Melting point: 66°-67.5° C.

REFERENCE EXAMPLE 18

20 Grams of p-tetrahydropyranyloxyiodobenzene and 70 ml of anhydrouspyridine containing 11.3 g of copper (I) 3-acetyloxy-1-propyn-1-ide wererefluxed for 6 hours under an atmosphere of argon gas. After thereaction was finished the reaction mixture was poured into water and thewhole mixture was extracted with chloroform. The chloroform layer waswashed with water, dried and the solvent was removed by evaporation. Theresidue thus obtained was purified by means of a silica gel columnchromatography (eluent: chloroform: n-hexane=1:1) to yield 8 g of4-[4-[2-tetrahydropyranyloxy)phenyl]-3-butynyl acetate in the form ofcolorless oily substance.

¹ H-NMR (60 MHz, CDCl₃) δ: 6.98 (2H, d, J=8Hz), 6.63 (2H, d, J=8Hz),6.15 (1H, m), 4.05 (2H, t, J=6Hz), 3.3-3.7 (2H, m), 2.58 (2H, t, J=6Hz),1.97 (3H, s), 1.5-1.9 (6H, m).

REFERENCE EXAMPLE 19

To an anhydrous tetrahydrofuran solution containing 2.4 g of4-[4-(2-tetrahydropyranyloxy)phenyl]-3-butynylacetate was added 1 g oflithium aluminium hydride and the mixture was refluxed for 12 hours.After the reaction was finished, a saturated sodium sulfate aqueoussolution was slowly added to the reaction mixture, and the precipitatesformed were removed by filtration, then the filtrate was dried withanhydrous sodium sulfate, and concentrated to dryness. The residue thusobtained was purified by means of a silica gel column chromatography toyield 2 g of 4-[(2-tetrahydropyranyloxy)phenyl]-3(E)-butenylalcohol asin the form of colorless oily substance.

¹ H-NMR (90 MHz, CDCl₃) δ: 1.5-2.1 (6H, m), 2.43 (2H, q, J=6Hz), 3.4-4.0(5H, m), 5.37 (1H, m), 6.03 (1H, d, t, J=16Hz, 6Hz), 6.40 (1H, d, J=16Hz), 6.97 (2H, d, J=9Hz), 7.25 (2H, d, J=9Hz).

REFERENCE EXAMPLE 20

15 Grams of 1-iodo-4-(1-ethoxyethoxy)benzene, 6 g of propargyl acetate,0.26 g of triphenylphosphine, 0.09 g of palladium chloride and 20 ml ofdiethylamine solution of cuprous iodide were stirred at 40°-50° C. for 1hour. After the reaction was finished, the reaction mixture was pouredinto water, and extracted with diethyl ether. The ether extract waswashed with water, dried and the solvent was removed by evaporation,then the residue thus obtained was purified by means of a silica gelcolumn chromatography (eluent: dichloromethane: n-hexane=1:1 anddichloromethane) to yield 10.1 g of3-[4-(1-ethoxyethoxy)phenyl]propargyl acetate.

N. M. R., (CDCl₃) δ: 1.17 (3H, t, J=7Hz), 1.47 (3H, d, J=5Hz), 2.09 (3H,s), 3.3-3.9 (2H, m), 4.87 (2H, s), 5.37 (1H, q, J=5Hz), 6.92 (2H, d,J=9Hz), 7.37 (2H, q, J=9Hz).

REFERENCE EXAMPLE 21

To 50 ml of methanol solution containing 10 g of3-[4-(1-ethoxyethoxy)phenyl]propargyl acetate, were added 1.5 g of5%-Pd-BaSO₄ and 10 drops of quinoline, and the mixture was catalyticallyreduced. After the reaction was finished, the reaction mixture wasfiltered, and the filtrate was allowed to evaporation, the residue thusobtained was purified by means of a silica gel column chromatography(eluent: dichloromethane and dichloromethane:methanol=100:1) to obtain 3g of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 4 g of4(Z)-hydroxycinnamyl acetate. Thus obtained 4 g of 4(Z)-hydroxycinnamylacetate was dissolved in 20 ml of anhydrous ether, to this solution wasadded 50 mg of p-toluenesulfonic acid and 10 ml of ethyl vinyl ether,and the whole mixture was refluxed for 3 hours. The reaction mixture wasthen washed with 5%-sodium hydroxide aqueous solution and water in thisorder, and dried. The solvent was removed by evaporation to yield 4.8 gof 4(Z)-(1-ethoxyethoxy)cinnamyl acetate.

N. M. R. (CDCl₃) δ: 1.21 (3H, t, J=7Hz), 1.50 (3H, d, J=5Hz), 2.09 (3H,s), 3.24-3.64 (1H, m), 3.70-3.90 (1H, m), 4.84 (2H, dd, J=6.5Hz, 1.5Hz),5.40 (1H, q, J=5Hz), 5.73 (1H, dt, J=11.5Hz, 6.5Hz), 6.60 (1H, dm,J=11.5Hz), 6.98 (2H, d, J=9Hz), 7.15 (2H, d, J=9Hz).

REFERENCE EXAMPLE 22

7.8 Grams of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 50 ml of methanolsolution containing 5 g of potassium carbonate were stirred at a roomtemperature for 2 hours. The solvent was removed by evaporation, and tothe residue thus obtained was added water and extracted with ether. Theether extract was washed with water, dried and the solvent remove byevaporation to yield 4(Z)-(1-ethoxyethoxy)cinnamyl alcohol.

N. M. R. (90 MHz, CDCl₃) δ: 1.19 (3H, t, J=7Hz), 1.48 (3H, d, J=5Hz),3.4-3.9 (2H, m), 4.39 (2H, dd, J=6Hz, J=2Hz), 5.36 (1H, q, J=5Hz), 5.75(1H, dt, J=11Hz, J=6Hz), 6.45 (1H, dm, J=11Hz), 6.95, 7.10 (4H, AB-q,J=9Hz).

REFERENCE EXAMPLE 23

8 Milliliters of 85% sodium hydroxide aqueous solution mixed with 46 gof ethylene glycol was heated at 40°-50° C., and 15 g of cinnamylbromide was added dropwise thereto. After the addition was finished, thereaction mixture was heated at 100°-110° C. for 2 hours. The reactionmixture was allowed to cool, and poured into 50 ml of water thenextracted with ether. The ether extract was washed with water and asaturated aqueous solution of sodium chloride in this order, and driedwith anhydrous sodium sulfate. The solvent was removed by evaporation,the residue thus obtained was purified by means of a silica gel columnchromatography (eluent: chloroform) to yield 5.5 g of 2-[3-phenyl-2(E)-propenyloxy]ethanol.

N. M. R. CDC13 (90 MHz) δ: 2.20 (1H, t, J=6Hz), 3.50-3.85 (4H, m), 4.18(2H, d, J=6Hz), 6.23 (1H, dt, J=6Hz, J=16Hz), 6.57 (1H, d, J=16Hz),7.20-7.50 (5H, m).

REFERENCE EXAMPLE 24

5.33 Grams of 60% sodium hydride was suspended in 25 ml ofdimethylformamide, and 9.3 ml of ethylene glycol was added dropwisethereto. After the addition was finished the reaction mixture wasstirred at 45° C. for 2 hours. The reaction mixture was ice-cooled, then6.5 g of 3-phenylpropargyl bromide was added dropwise to the reactionmixture and stirred at the same temperature for 1 hour. After thereaction was finished, the reaction mixture was poured into 200 ml ofwater, and the whole mixture was extracted with ether. The ether extractwas washed with water and dried with anhydrous magnesium sulfate, andthe solvent was removed by evaporation. The residue thus obtained waspurified by means of a silica gel column chromatography(eluent:chloroform:n-hexane=3:1) to yield 2.4 g of2-(3-phenyl-2-propionyloxy)ethanol. Refractive index: n_(D) ²⁴ 1.5590.

REFERENCE EXAMPLE 25

6.5 Grams of propargyl bromide, 0.32 g of tetrabutylammonium bromide and2.7 g of sodium hydroxide were dissolved in 20 ml of methylene chlorideand 8 ml of water, and this solution was refluxed for 2 hours. After thereaction mixture was cooled, the organic layer was collected byseparation, washed with water, dried with anhydrous magnesium sulfate.The solvent was removed by evaporation, the residue thus obtained waspurified by means of a silica gel column chromatography (eluent:chloroform:n-hexane =2:1) to yield 4.0 g of2-(3-phenyl-2-propionylthio)ethanol. Refractive index: n_(D) ²² 1.6078.

REFERENCE EXAMPLE 26

4.3 Grams of 2-mercaptoethanol, 10 ml of 40% sodium hydroxide aqueoussolution, 0.2 g of tetrabutylammonium bromide and 40 ml of methylenechloride were heated at 40°-45° C., then 20 ml of methylene chloridesolution containing 10 g of cinnamyl bromide was added dropwise thereto.The reaction mixture was stirred vigorously at the same temperature for4-5 hours. The organic layer was collected by separation and washed withwater, dried with anhydrous sodium sulfate. The solvent was removed byevaporation, the residue thus obtained was distilled under a reducedpressure to yield 8.6 g of 2-(3-phenyl-2(E)-propionylthio)ethanol.Boiling point: 150°-153° C. (1 mm Hg).

N. M. R. CDCl₃ (90 MHz) δ: 2.16 (1H, t, J=6Hz), 2.70 (2H, t, J=6Hz),3.30 (2H, d, J=6Hz), 3.70 (2H, q, J=6Hz), 6.14 (1H, dt, J=6Hz, J=16Hz),6.40 (1H, d, J=16Hz), 7.20 - 7.60 (5H, m).

REFERENCE EXAMPLE 27

12.5 Grams of cinnamyl chloride and 21 g of 2-methylaminoethanol weredissolved in 100 ml of ethanol, and the solution was refluxed for 5hours. The solvent was removed by evaporation, to the residue thusobtained was added water and washed with n-hexane. To the water layerwas added 3N-sodium hydroxide aqueous solution to adjust its pH to10-11, and extracted with ether. The ether extract was washed with waterand dried with anhydrous sodium sulfate, and the solvent was removed byevaporation. The residue was purified by means of a silica gel columnchromatography (eluent: chloroform: methanol=25:1) to yield 15 g of2-[N-methyl-N-(3-phenyl-2(E)-propenyl)amino]ethanol.

N. M. R. CDCl₃ (90 MHz) δ: 2.30 (3H, s), 2.55 (2H, t, J=7Hz), 2.90 (1H,s), 3.20 (2H, d, J=7Hz), 3.60 (2H, t, J=7Hz), 6.20 (1H, dt, J=7Hz,J=16Hz), 6.48 (1H, d, J=16Hz), 7.25-7.50 (5H, m).

REFERENCE EXAMPLE 28

By a method similar to that described in Reference Example 27, by usinga suitable starting material, the following compound was prepared.

2-[N-Methyl-N-(3-phenyl-2-propynyl)amino]ethanol

Boiling point: 124°-126° C. (1m2 mm Hg)

Refractive index: n_(D) ²⁴ 1.5589

REFERENCE EXAMPLE B 29

5 Grams of cinnamyl bromide, 5 g of anhydrous piperazine and 50 ml ofacetone solution containing 8.4 g of anhydrous potassium carbonate wererefluxed for 6 hours. To the reaction mixture was added water and thewhole mixture was extracted with chloroform. The chloroform layer waswashed with water, dried and the solvent was removed by evaporation. 2.2Grams of 1-acetyl-4-cinnamylpiperazine thus obtained was dissolved in80% of methanol, and 2 g of potassium hydroxide was added thereto, thenthe mixture was refluxed for 8 hours. To the reaction mixture was addedwater, and the whole mixture was extracted with chloroform, washed withwater, dried, and chloroform was removed by evaporation. The residuethus obtained was purified by means of a silica gel columnchromatography (eluent: chloroform and chloroform:methanol=30:1) toyield 1.2 g of N-cinnamylpiperazine.

N. M. R. CDCl₃ δ: 2.34 (1H, s), 2.46 (4H, m, J=5Hz), 2.92 (4H, m, J=5Hz), 3.13 (2H, d, J=6Hz), 6.23 (1H, dt, J=15Hz, 6Hz), 6.82 (1H, d,J=15Hz), 7.2-7.5 (5H, m).

REFERENCE EXAMPLE 30

To 150 ml of anhydrous carbon tetrachloride solution containing 116 g ofmethyl acetoacetate was added dropwise 51 ml of bromine at below 5° C.After the addition was finished the reaction mixture was stirredovernight, then the reaction mixture was poured into ice-water, washedwith a diluted sodium carbonate aqueous solution five times, then with asaturated sodium chloride aqueous solution, and dried with anhydrouscalcium chloride. The solvent was removed by evaporation to yield 170 gof methyl 4-bromoacetoacetate.

REFERENCE EXAMPLE 31

1.6 Grams of 60% sodium hydride was suspended in 80 ml of anhydrousdimethoxyethane, then 40 ml of dimethoxyethane solution containing 8 gof methyl 4-bromoacetoacetate was added dropwise thereto at -40 to -50°C. At the same temperature, lithium N-methylcinnamylamide prepared from20 ml of dimethoxyethane solution containing 5.9 g ofN-methylcinnamylamine and 40 ml of 1N-n-butyl lithium was addeddropwise. After the addition was finished, the reaction mixture wasstirred at 65°-70° C. for 15 hours. The reaction mixture was poured intoan ice-water and the whole mixture was extracted with diethyl ether. Theextract was washed with water, dried and the solvent was removed byevaporation, the residue thus obtained was purified by means a silicagel column chromatography (eluent: dichloromethane anddichloromethane:methanol= 50:1) to yield 1.8 g of4-(N-methyl-E-cinnamylamino)acetoacetate.

N. M. R. CDCl₃ δ: 2.32 (3H, s), 3.22 (2H, d, J=6Hz), 3.31 (2H, s), 3.51(2H, 2), 3.68 (3H, s}, 6.18 (1H, dt, J=16Hz, 6Hz), 6.50 (1H, d, J=16Hz),7.0-7.5 (5H, m).

REFERENCE EXAMPLE 32

4 Grams of 60% sodium hydride was suspended in 150 ml of anhydrousdimethoxyethane and the suspension was cooled to -30° C. Then, 19.4 g ofmethyl 4-bromoacetoacetate was added dropwise to the suspension andstirred for 1 hour. Further, at the same temperature, an anhydrousdimethoxyethane solution of sodium cinnamy alcoholate prepared from 13.4g of cinnamyl alcohol, 4 g of 60% of sodium hydride and 75 ml ofdimethoxyethane was added dropwise thereto, and the reaction mixture wasrefluxed for 15 hours. After the reaction mixture was cooled to a roomtemperature, the reaction mixture was poured into 1N-hydrochloric acidbeing ice-cooled, and the whole mixture was extracted with ether. Theether extract was washed with water and dried with anhydrous sodiumsulfate, and the solvent was removed by evaporation. The residue waspurified by means of a silica gel column chromatography (eluent:methanol:dichloromethane=1:20) to yield 6 g of methyl4(E)-cinnamyloxyacetoacetate Refractive index: n_(D) ²⁰ 1.5402

REFERENCE EXAMPLE 33

By a method similar to that described in Example 32, by using a suitablestarting material, there was prepared the following compounds.

Methyl 4-[4(E)-(1-ethoxyethoxy)cinnamyloxy]acetoacetate

Refractive index: n_(D) ²⁰ =1.5232

REFERENCE EXAMPLE 34

A mixture of 9 g of 4(E)-(1-ethoxyethoxy)cinnamyl alcohol and 0.5 ml oftriethylamine was heated at 70°-80° C., and 6 g of diketene was slowlyadded dropwise thereto. After the addition was finished, the reactionmixture was heated at 110°-120° C. for 30 minutes. After the reactionwas completed, the solvent was removed by evaporation under a reducedpressure, and the residue thus obtained was purified by means of asilica gel column chromatography (eluent: diethyl ether: n-hexane=1:3)to yield 8.8 g of 4(E)-[1-ethoxyethoxy)cinnamyl acetoacetate. Refractiveindex: _(D) ²⁴ 1.5305

N. M. R. CDCl₃ (90 MHz) δ: 1.17 (3H, t, J=7Hz), 1.48 (3H, d, J=6Hz),2.25 (3H, s), 3.48 (2H, s), 3.40-3.85 (2H, m), 4.75 (2H, d, J=6Hz), 5.36(1H, q, J=6Hz), 6.18 (1H, dt, J=6Hz, J=16Hz), 6.94 (2H, d, J=9Hz), 7.28(2H, d, J=9Hz).

REFERENCE EXAMPLE 35

To 400 ml of acetonitrile solution containing 30 g of 2-iodoethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate wasa of piperazine, and the mixture was stirred at a room temperatureovernight. After the reaction was finished, the insoluble matters wereremoved by filtration, then chloroform was added to the filtrate, thechloroform layer was washed with a saturated sodium hydrogen carbonateaqueous solution and water in this order, and dried with anhydroussodium sulfate. The reaction mixture was concentrated by evaporating thesolvent, and the residue thus obtained was purified by means of a silicagel column chromatography (eluent:dichloromethane:methanol:triethylamine=100:10:1) to yield 21 g of methyl5-[2-(1-pip2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate asin the form of light yellow indefinite form crystals.

N. M. R. CDCl₃ (200 MHz) δ: 1.892 (1H, bs), 2.366 (3H, s), 2.379 (3H,s), 2.40-2.50 (4H, m), 2.52-2.60 (2H, m), 2.80-2.90 (4H, m), 3.651 (3H,s), 4.08-4.28 (2H, m), 5.109 (1H, s), 5.947 (1H, bs), 7.3-8.2 (4H, m).

REFERENCE EXAMPLE 36

18.6 Grams of 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione and 50 mltetrahydrofuran solution containing 22.2 g of 4-(1-ethoxyethoxy)cinnamylalcohol were refluxed for 6 hours. After the reaction was completed, thesolvent was removed by evaporation, and the residue thus obtained waspurified by means of a silica gel column chromatography (eluent: ethylacetate:n-hexane=1:4) to yield 5.8 g of 4-[(1-ethoxy)ethoxy]cinnamylacetoacetate as in the form of an oily substance.

N. M. R. (CDCl₃) δ: 1.15 (3H, t, J=7Hz), 1.44 (3H, d, J=5.4Hz), 2.20(3H, s), 3.31-3.95 (2H, m), 3.45 (2H, s), 4.71 (2H, d, J=6Hz), 5.35 (1H,q, J=5.2Hz), 6.10 (1H, dt, J=6.1Hz, 15.3Hz), 6.59 (1H, d, J=15.3Hz),6.91 (2H, d, J=9Hz), 7.29 (2H, d, J=9Hz).

IR (film): ν: 1650, 1730⁻¹.

EXAMPLE 1

5.4 Grams of 4-(2-tetrahydropyranyloxy)cinnamyl alcohol, 11.5 g of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic7.1 g of DCC were dissolved in 30 ml of pyridine, and the reactionmixture was stirred at a room temperature overnight. 200 Milliliters ofwater was added to the reaction mixture and extracted with ethylacetate. The extract was washed with water, a saturated potassiumhydrogen sulfate aqueous solution, water and a saturated sodium chlorideaqueous solution in this order, then dried and the solvent was removedby evaporation. The residue thus obtained was purified by means a silicagel column chromatography (eluent: chloroform) to yield 3.4 g of methyl3-(4-tetrahydropyranyloxyphenyl)-2(E)-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate.

N. M. R. δ (CDCl₃): 1.4-2.0 (6H, m), 2.26 (6H, m), 3.53 (3H, s), 3.4-4.0(2H, m), 4.58 (2H, d, J=6Hz), 5.03 (1H, s), 5.30 (1H, t, J=3Hz), 5.97(1H, dt, Ja=6Hz, Jb=16Hz), 6.30 (1H, bs), 6.37 (1H, d, J=16Hz), 6.88(2H, d, J=9Hz), 7.14 (2H, d, J=9Hz), 7.20 (1H, t, J=6Hz), 7.50 (1H, dt,Ja=2Hz, Jb=6Hz), 7.82 (1H, dt, Ja=2Hz, Jb=tHz), 8.00 (1H, t, J=2Hz).

EXAMPLE 2

3.4 Grams of methyl 3-(4-tetrahydropyranyloxyphenyl)-2(E}-propenyl1,4-dihydro-2,6-dimethyl-4-(3,5-dicarboxylate was dissolved 50 ml ofmethanol, then 0.2 g of p-toluenesulfonic acid was added to the solutionand the whole mixture was stirred at a room temperature for 4 hours. Thereaction mixture was neutralized by adding sodium hydrogen carbonate,and methanol was removed by evaporation. The residue thus obtained waspurified by means of a silica gel column chromatography (eluent:chloroform), recrystallized from benzene-ether to yield 2 g of methyl3-(4-hydroxyphenyl)-2(E)-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate asin the form of light yellow powdery substance. Melting point:137.5°-139° C.

EXAMPLE 1

To 20 ml of an anhydrous methylene chloride solution containing 1.6 g oftetramethylurea was added 1.9 g of oxalyl chloride at a room temperatureand the mixture was refluxed for 2 hours, then 4.3 g of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid was added thereto, under an ice-cooled and stirred condition whilethe raction mixture was as in a suspended state, 1.7 g of3-p-(2-tetrahydropyranyloxy)phenylpropargyl alcohol in 10 ml ofanhydrous methylene chloride solution was added to the suspension andthe whole mixture was stirred at a room temperature for 3 hours. Underan ice-cooled condition, the reaction mixture was poured in1N-hydrochloric acid, and the organic layer was washed with water inthree times and dried with anhydrous sodium sulfate, then solvent wasremoved by evaporation. The residue thus obtained was purified by meansof a silica gel column chromatography (eluent: chloroform) to yield 2.8g of methyl 3-[4-(2-tetrahydropyranyloxyphenyl)]-2-propynyl1,4-dihydro-2,6-dimethyl-4 -(3-nitrophenyl)pyridine-3,5-dicarboxylate inthe form of light yellow indefinite form crystals.

EXAMPLE 4

2.7 Grams of methyl 3-[4-(4-tetrahydropyranyloxyphenyl)]-2-propynyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate wasdissolved in 30 ml of methanol, then 10 mg of p-toluenesulfinic acid wasadded and the mixture was stirred for 1 hour. The reaction mixture wasneutralized by adding a saturated sodium hydrogen carbonate aqueoussolution, further 100 ml of water was added then the mixture wasextracted with chloroform. The chloroform layer was washed with water inthree times, then dried with anhydrous sodium sulfate, the solvent wasremoved by evaporation. The residue thus obtained was purified by meansof a silica gel column chromatography (eluent: ethylacetate:n-hexane=4:1), next recrystallized from tetrahydrofuran-n-hexaneto yield 1.2 g of methyl3-(4-hydroxyphenyl)-2-propynyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylicin the form of yellow prism-like crystals.

Melting point: 173°-176° C.

EXAMPLE 5

To a mixture consisting of 1.9 of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid, 0.78 ml of 30% sodium hydroxide aqueous solution and 15 ml of HMPAwere added dropwise 1.5 g of 4-(4-methylthiophenyl)-3(E)-butenylbromide. The mixture was stirred at a room temperature for 8 hours, thenat 40°-45° C. for 5 hours, next the reaction mixture was poured into anice-water and extracted with chloroform. The chloroform layer was washedwith water, then dried with anhydrous sodium sulfate, and the solventwas removed by evaporation. The residue thus obtained was purified bymeans of a silica gel column chromatography (eluent: ethylacetate:n-hexane=1:2), recrystallization from ethyl acetate-n-hexane toyield 1.0 g of methyl 4-(4-methylthiophenyl)-3(E)-butenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-yridine-3,5-dicarboxylate inthe form of light yellow powdery substance. Melting point: 165°-170° C.

EXAMPLE 6

3.36 Grams of1-[2(E)-acetoacetocymethylvinyl]-4-(2-tetrahydropyranyloxy)benzene, 1.5g of 3-nitrobenzaldehyde and 1.2 g of methyl 3-aminocrotonate were addedto 20 ml of isopropanol, and the mixture was refluxed for 8 hours. Thereaction mixture was concentrated and the residue was purified by meansof a silica gel column chromatography (eluent: chloroform) to yield 1.2g of methyl 3-[4-tetrahydropyranyloxyphenyl)-2(E)-propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate.

N. M. R. δ (CDCl₃): 1.4-2.0 (6H, m), 2.26 (6H, m), 3.53 (3H, s), 3.4-4.0(2H, m), 4.58 (2H, d, J=6Hz), 5.03 (1H, s), 5.30 (1H, t, J=3Hz), 5.97(1H, dt, Ja=6Hz, Jb=16H), 6.30 (1H, bs), 6.37 (1H, d, J=16Hz), 6.88 (2H,d, J=9Hz), 7.14 (2H, d, J=9Hz), 7.20 (1H, t, J=6Hz), 7.50 (1H, dt,Ja=2Hz, Jb=6Hz), 7.82 (1H, dt, Ja=2Hz, Jb=6Hz), 8.00 (1H, t, J=2Hz).

EXAMPLES 7-30

By using a suitable starting material, and by methods similar to thosedescribed in Examples 1 and 6, there were prepared compounds as shown inTable 1 as follows.

    TABLE 1      ##STR35##             Melting point (°C.)   Example      (Recrystallization No.     R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 solvent) Crystal form Salt                7 CH.sub.3 CH.sub.3      ##STR36##      CH.sub.3      ##STR37##      137.5-139(Ether-benzene) YellowpowderycrystalsIR.sup.1) --  8 CH.sub.3     CH.sub.3      ##STR38##      CH.sub.3      ##STR39##      60-63(Ether--n-hexane) Light yellowpowderycrystals --  9 CH.sub.3     CH.sub.3      ##STR40##      CH.sub.3      ##STR41##      75-105(Ether--n-hexane) Light yellowindefiniteformcrystals --  10     CH.sub.3 CH.sub.3      ##STR42##      CH.sub.3      ##STR43##      181-182(Methanol) Yellowpowderycrystals --  11 CH.sub.3 CH.sub.3      ##STR44##      CH.sub.3      ##STR45##      173-176(Tetrahydrofuran--n-hexane)  Yellowprism-likecrystals --  12     CH.sub.3 CH.sub.3      ##STR46##      CH.sub.3      ##STR47##      170-171(Methanol) Light yellowpowderycrystals --  13 CH.sub.3 CH.sub.3      ##STR48##      CH.sub.3      ##STR49##      90-95(Tetrahydrofuran--n-hexane) Light yellowindefiniteformcrystals --     14 CH.sub.3 CH.sub.3      ##STR50##      CH.sub.3      ##STR51##      164-165(Methanol-ether) Light yellowpowderycrystals --  15 CH.sub.3     CH.sub.3      ##STR52##      CH.sub.3      ##STR53##      146-153(Isopropanol) Yellowpowderycrystals --  16 CH.sub.3 CH.sub.3      ##STR54##      CH.sub.3      ##STR55##      165-170(Ethyl acetate--n-hexane) Light yellowindefiniteformcrystals --     17 CH.sub.3 CH.sub.3      ##STR56##      CH.sub.3      ##STR57##      145-150(Ethyl acetate--n-hexane) Yellowindefiniteformcrystals --  18     CH.sub.3 CH.sub.3      ##STR58##      CH.sub. 3      ##STR59##      68-70(Ether--n-hexane) Light yellowpowderycrystals --  19 CH.sub.3     CH.sub.3      ##STR60##      CH.sub.3      ##STR61##      NMR.sup.1) Light yellowindefiniteformcrystals --  20 CH.sub.3 CH.sub.3      ##STR62##      CH.sub.3      ##STR63##      NMR.sup.2) Light yellowindefiniteformcrystals --  21 CH.sub.3 CH.sub.3      ##STR64##      CH.sub.3      ##STR65##      NMR.sup.3) Light yellowindefiniteformcrystals --  22 CH.sub.3 CH.sub.3      ##STR66##      CH.sub.3      ##STR67##      NMR.sup.4) Light yellowindefiniteformcrystals --  23 CH.sub.3 CH.sub.3      ##STR68##      CH.sub.3      ##STR69##      NMR.sup.5) Light yellowindefiniteformcrystals --  24 CH.sub.3 CH.sub.3      ##STR70##      CH.sub.3      ##STR71##      NMR.sup.6) Light yellowindefiniteformcrystals --  25 CH.sub.3 CH.sub.3      ##STR72##      CH.sub.3      ##STR73##      NMR.sup.7) Yellowindefiniteformcrystals --  26 CH.sub.3 CH.sub.3      ##STR74##      CH.sub.3      ##STR75##      NMR.sup.8) Light yellowindefiniteformcrystals --  27 CH.sub.3 CH.sub.3      ##STR76##      CH.sub.3      ##STR77##      NMR.sup.9) Light yellowindefiniteformcrystals --  28 CH.sub.3 CH.sub.3      ##STR78##      CH.sub.3      ##STR79##      NMR.sup.10) Light yellowindefiniteformcrystals --  29 CH.sub.3 CH.sub.3      ##STR80##      CH.sub.3      ##STR81##      120.5-121.5(Tetrahydrofuran--n-hexane) Yellowpowderycrystals --  30     CH.sub.3 CH.sub.3      ##STR82##      CH.sub.3      ##STR83##      122-124(Tetrahydrofuran--n-hexane) Light yellowpowderycrystals --  31     CH.sub.3 CH.sub.3      ##STR84##      CH.sub.3      ##STR85##      92-95(Chloroform--n-hexane) Light yellowpowderycrystals --  32 CH.sub.3     CH.sub.3      ##STR86##      CH.sub.3      ##STR87##      NMR.sup.12) Yellow oilysubstance --      33 CH.sub.3 CH.sub.3     ##STR88##      CH.sub.3      ##STR89##      170-172(Ether--n-hexane) Light Yellowprism-likecrystals --  34 CH.sub.3     CH.sub.3      ##STR90##      CH.sub.3      ##STR91##      181-182(Acetone) Light yellowprism-likecrystals --  35 CH.sub.3     CH.sub.3      ##STR92##      CH.sub.3      ##STR93##      168-172 (methanol) Light yellowpowderycrystals --  36 CH.sub.3 CH.sub.3      ##STR94##      CH.sub.3      ##STR95##      175-177(Tetrahydrofuran) Light yellowpowderycrystals --  37 CH.sub.3     CH.sub.3      ##STR96##      CH.sub.3      ##STR97##      197-198(Acetone) Light yellowpowderycrystals --  38 CH.sub.3 CH.sub.3      ##STR98##      CH.sub.3      ##STR99##      102.5-105(Methylenechloride) Light yellowpowderycrystals --  39     CH.sub.3 CH.sub.3      ##STR100##      C.sub. 2      H.sub.5     ##STR101##      145-148(Methanol) Light yellowprism-likecrystals --  40 CH.sub.3     CH.sub.3      ##STR102##      ##STR103##      ##STR104##      158-159(Chloroform) Light yellowpowderycrystals --  41 CH.sub.3      ##STR105##      ##STR106##      CH.sub.3 CH.sub.3 121-122(Ether) Light yellowpowderycrystals --  42     CH.sub.3      ##STR107##      ##STR108##      CH.sub.3 CH.sub.3 142- 145(Methanol) Light yellow 1/2.H.sub.2 O  43     CH.sub.3      ##STR109##      ##STR110##      CH.sub.3 CH.sub.3 137-140(Methanol) Yellowpowderycrystals 1/2.H.sub.2 O      44 CH.sub.3     ##STR111##      ##STR112##      CH.sub.3 CH.sub.3 101.5-115(Ethyl acetate-ether)NMR.sup.13) Yellowpowder     ycrystals HCl.H.sub.2 O      45 CH.sub.3 CH.sub.3     ##STR113##      CH.sub.3      ##STR114##      194-196(Methanol) Light yellowneedle-likecrystals --  46 CH.sub.3     CH.sub.3      ##STR115##      CH.sub.3      ##STR116##      157-158(Methanol) Light yellowneedle-likecrystals --  47 CH.sub.3     CH.sub.3      ##STR117##      CH.sub.3      ##STR118##      75-90(Ether--n-hexane)NMR.sup.14) Light yellowpowderycrystals --  48     CH.sub.3 CH.sub.3      ##STR119##      CH.sub.3      ##STR120##      82-85(Ether--n-hexane) Light yellowpowderycrystals --  49 CH.sub.3     CH.sub.3      ##STR121##      CH.sub.3      ##STR122##      96-102(Ether--n-hexane) Light yellowpowderycyrstals --  50 CH.sub.3     CH.sub.3      ##STR123##      CH.sub.3      ##STR124##      81.5-83(Ethyl acetate-diisopropylether) Light yellowpowderycrystals --     51 CH.sub.3 CH.sub.3      ##STR125##      CH.sub.3      ##STR126##      77.5-78.5(Ethyl acetate-diisopropylether) Light yellowpowderycrystals     --      52 CH.sub.3 CH.sub.3     ##STR127##      CH.sub.3      ##STR128##      NMR.sup.15) -- --      53 CH.sub.3 CH.sub.3     ##STR129##      CH.sub.3      ##STR130##      NMR.sup.16) Light yellowindefiniteformcrystals --  54 CH.sub.3 CH.sub.3      ##STR131##      CH.sub.3      ##STR132##      115-116(Ethyl acetate-diisopropylether) Light yellowpowderycrystals --     55 CH.sub.3 CH.sub.3      ##STR133##      CH.sub.3      ##STR134##      115-116(Ethyl acetate-diisopropylether) Light yellowpowderycrystals --     56 CH.sub.3 CH.sub.3      ##STR135##      CH.sub.3      ##STR136##      168-169(Acetone) Light yellowpowderycrystals HCl  57 CH.sub.3 CH.sub.3      ##STR137##      CH.sub.3      ##STR138##      NMR.sup.17) Yellowindefiniteformcrystals --  58 CH.sub.3 CH.sub.3      ##STR139##      CH.sub.3      ##STR140##      154-158(Chloroform--n-hexane) Light yellowpowderycrystals 2HCl.H.sub.2     O      59 CH.sub.3 CH.sub.3     ##STR141##      CH.sub.3      ##STR142##      217-220(Ethyl acetate-methanol-water) Light yellowneedle-likecrystals     2HCl      60 CH.sub.3 CH.sub.3     ##STR143##      CH.sub.3      ##STR144##      62-68NMR.sup.18) Yellowindefiniteformcrystals  61 CH.sub.3 CH.sub.3      ##STR145##      CH.sub.3      ##STR146##      144-146(Diisopropylether-ethanol) Light yellowpowderycrystals HCl  62     CH.sub.3 CH.sub.3      ##STR147##      CH.sub.3      ##STR148##      NMR.sup.19 -- --       (*)OTHP: 2-tetrahydropyranyloxy group IR.sup.1) 1660, 1680, 1700     cm.sup.-1 NMR.sup.1) (90MHz, CDCl.sub.3): 2.28(3H, s), 2.35(6H, s),     3.64(3H, s), 4.67(2H, d, J=7Hz), 5.12(1H, s), 6.60(1H, broad, s),     6.15(1H, d, t, Ja=7H, Jb=16Hz), 6.50(1H, d, J=16Hz), 7.03(2H, d, J=8Hz),     7.30(2H, d, J=8Hz), 7.32(1H, t, J=8Hz), 7.63(1H, dt, Ja=2Hz, Jb=8Hz),     7.97(1H, d, t, Ja=2Hz, Jb=8Hz), 8.12(1H, t, J=2Hz) NMR.sup.2) (90MHz,     CDCl.sub.3): 1.45-2.10(6H, m), 2.30(6H, t), 3.40-4.00(2H, m), 3.56(3H,     s), 4.63(2H, d, J=6Hz), 5.10(1H, s), 5.37(1H, t, J=3Hz),m 6.17(1H, d, t,     Ja=6Hz, Jb=16Hz), 6.45(1H, d, J=16Hz), 6.65-7.20(4H, m), 7.30(1H, t,     J=7Hz), 7.62(1H, d, t, Ja=2Hz, Jb=7Hz), 7.95(1H, d, t, Ja=2Hz, Jb=7Hz),     8.13(1H, t, J=2Hz) NMR.sup.3) (90MHz, CDCl.sub.3): 2.30(3H, s), 2.32(3H,     s), 3.38(3H, s), 3.53(3H, sl, 4.65(2H, d, J=7Hz), 5.10(1H, s), 5.13(2H,     s), 6.20(1H, dt, Ja=6Hz, Jb=16Hz), 6.47(1H, s), 6.87(1H, d, J=16Hz),     6.87-7.48(5H, m), 7.62(1H, dt, Ja=2Hz, Jb=7Hz), 7.93(1H, dt, Ja=2Hz,     Jb=7Hz), 8.12(1H, t, J=2Hz) NMR.sup.4) (90MHz, CDCl.sub.3): 1.50-     1.95(6H, m), 1.97(3H, s), 2.32(6H, s), 3.34-3.90(1H, m), 3.53(3H, s),     4.65(2H, d, J=7Hz), 5.03(1H, s), 5.33(1H, t, J=3Hz), 5.70(1H, t, J=7Hz),     5.95(1H, broad, s), 6.97(2H, d, J=9Hz), 7.23(2H, d, J=9Hz), 7.28(1H, t,     J=7Hz), 7.58(1H, d, t, Ja=2Hz, Jb=7Hz), 7.93(1H, dt, Ja=2Hz, Jb=7Hz),     8.08(1H, t, J=2Hz) NMR.sup.5) (90MHz, CDCl.sub.3): 1.30-2.0(6H, m),     2.32(6H, s), 3.53(3H, s), 3.3-3.95(2H, m), 4.79(2H, s), 5.07(1H, s),     5.33(1H, t, J=3Hz), 6.02(1H, s), 6.93(2H, d, J=10Hz), 7.28 (2H, d,     J=10Hz), 7.27(1H, t, J=8Hz), 7.66(1H, d, J=8Hz), 7.93(1H, d, J=8Hz),     8.10(1H, s) NMR.sup.6) (90MHz, CDCl.sub.3): 1.40-2.10(6H, m), 2.32(6H,     s), 3.43(3H, s), 3.20-3.85(2H, m), 4.43(2H, d, J=7Hz), 4.95(1H, s),     5.23(1H, t, J=3Hz), 5.04-5.80(1H, ml, 5.93-6.53(3H, m), 6.60(1H, s),     6.87(2H, d, J=10Hz), 7.20(2H, d, J=10Hz), 7.23(1H, t, J=8Hz), 7.53(1H,     d, t, Ja=2Hz, Jb=8Hz), 7.88(H, d, t, Ja=2Hz, Jb=8Hz) NMR.sup.7) (60MHz,     CDCl.sub.3): 1.40-2.0(6H, m), 2.30(3H, s), 2.33(3H, s), 3.20-3.90(2H,     m), 3.60(3H, s), 4.63(2H, d, J=6Hz), 5.37(1H, t, J=3Hz), 5.80(1H, s),     6.03(1H, d, t, Ja=6Hz, Jb=16Hz, 6.80(1H, s), 6.38(1H, d, J=16Hz),     6.90(2H, d, J=9Hz), 7.20(2H, d, J=9Hz), 6.75-7.80(4H, m) NMR.sup.8)     (90MHz, CDCl.sub.3): 1.43-2.15(6H, m), 2.30(6H, s), 3.38(3H, s),     3.20-3.80(2H, m), 4.47(2H, dd, Ja=3Hz, Jb=7Hz), 5.23(1H, t, J=3Hz),     5.43(1H, s), 6.83(1H, broad, s), 5.94 (1H, dt, Ja=6Hz, Jb=16Hz),     6.23(1H, d, J=16Hz), 6.87(2H, d, J=9Hz), 7.13(2H, d, J=9Hz), 6.75-7.60(4H     , m) NMR.sup.9) (90MHz, CDCl.sub.3): 1.5-2.1(6H, m), 2.28(3H, s),     3.53(3H, s), 3.76(3H, s), 3.4-4.1(1H, m), 4.57(2H, d, J=6Hz), 5.27(1H,     t, J=3Hz), 5.99(1H, dt, Ja=6Hz, Jb=16Ha), 6.07(1H, s), 6.36(1H, d,     J=16Hz), 6.73(1H, d, J=7Hz), 6.78(1H, s), 6.93(1H, D, J=7Hz), 7.18(1H,     t, J=7Hz), 7.50(1H, dt, Ja=2Hz, Jb=7Hz), 7.83(1H, dt, Ja=2Hz, Jb=7Hz),     7.99(1H, t, J=2Hz) NMR.sup.10) (60MHz, CDCl.sub.3): 1.24(3H, t, J=7Hz),     2.37(3H, s), 3.66(3H, s), 3.79(2H, q, J=7Hz), 4.70(2H, d, J=6Hz),     5.16(1H, s), 5.30(2H, s), 5.91(1H, broad, s), 6.10(1H, dt, Ja=6Hz,     Jb=16Hz), 6.4091H, d, J=16Hz), 7.00-7.47(4H, m), 7.64(1H, dt, Ja=2Hz,     Jb=7Hz), 7.97(1H, dt, Ja=2Hz, Jb=7Hz), 8.14(1H, t, J=2Hz) NMR.sup.11)     (90MHz, CDCl.sub.3): 1.40-2.10(6H, m), 2.26(6H, m), 3.53(3H, s),     3.40-4.0(2H, m), 4.58(2H, d, J=6Hz), 5.03(1H, s), 5.30(1H, t, J=3Hz),     5.97(1H, dt, Ja=6Hz, Jb=16Hz), 6.30(1H, broad, s), 6.37(1H, d, J=16Hz),     6.88(2H, d, J=9Hz,), 7.14(2H, d, J=9Hz), 7.20(1H, t, J=6Hz), 7.50(1H,     dt, Ja=2Hz, Jb=6Hz), 7.82(1H, dt, Ja=2Hz, Jb=6Hz), 8.00(1H, t, J=2Hz)     NMR.sup.12) (90MHz, CDCl.sub.3): 1.5-2.1(6H, m), 2.33(6H, s), 2.48(2H,     q, J=6Hz), 3.58(3H, s), 3.5-4.0(2H, m), 4.15(2H, t, J=6Hz), 5.09(1H, s),     5.40(1H, m), 5.93(1H, d, t, J=15Hz, 6Hz), 6.30(1H, s), 6.32(1H, d,     J=15Hz), 6.96(2H, d, J=9Hz), 7.19(2H, d, J=9Hz), 7.1-7.3(1H, m),     7.5-7.7(1H, d, m, J=6Hz), 7.8-8.0(1H, D, m, J=6Hz), 8.10(1H, m) NMR.sup.1     3) (90MHz, CDCl.sub.3): 2.36(3H, s), 2.40(3H, s), 3.25(2H, d, J=6Hz),     3.63(6H, s), 3.6-3.9(2H), 5.10(1H, s), 6.20(1H, dt, J=16Hz, 6Hz),     6.53(1H, d, J=16Hz), 7.1-8.3(10H, m) NMR.sup.14) (90MHz, CDCl.sub.3):     2.36(9H, s), 2.75(2H, t, J=6Hz) 3.53(2H, s), 3.62(3H, s), 4.16(2H, t,     J=6Hz), 5.11(1H, s), 5.75(1H, bs), 7.20-8.20(9H, m) NMR.sup.15) (90MHz,     CDCl.sub.3): 2.33(6H, s), 2.93(2H, t, J=6Hz), 3.48(2H, s), 3.63(3H, s),     4.30(2H, t, J=6Hz), 5.11(1H, s), 6.22(1H, s), 7.20-7.50(6H, m), 7.66(1H,     dt, J=8Hz, J=2Hz), 7.93(1H, bd, J=8Hz), 8.12(1H, t, J=Hz) NMR.sup.16)     (90MHz, CDCl.sub.3): 2.35(6H, s), 3.60(3H, s), 3.75(2H, t, J=5Hz),     4.17-4.33(2H, m), 4.36(2H, s), 5.11(1H, s), 5.80(1H, bs), 7.20-8.20(9H,     m) NMR.sup.17) (90MHz, CDCl.sub.3): 2.20(3H, s), 2.27(3H, s), 2.30(3H,     s), 2.62(2H, t, J=6Hz), 3.51(3H, s), 4.18(2H, m), 5.72(1H, s), 5.82(1H,     bs), 6.18(1H, dt, J=6Hz, J=16Hz), 6.43(1H, d, J=16Hz), 7.10-7.55(8H, m),     7.62(1H, d, J=7.5Hz) NMR.sup.18) (90MHz, CDCl.sub.3): 2.37(6H, s),     3.64(3H, s), 4.87(2H, s), 5.13(1H, s), 6.20(1H, brs), 6.94(1H, dd,     J=4.5Hz, J=4Hz), 7.1-7.4(3H, m), 7.64(1H, d-m, J=8Hz) 7.97(1H, d-m     J=8Hz), 8.10(1H, t, J=2Hz) NMR.sup.19) (90MHz, CDCl.sub.3): 1.17(3H, t,     J=7Hz), 1.47(3H, d, J=5.5Hz), 2.34(6H, s), 3.35-3.95(2H, m), 3.60(3H,     s), 4.65(2H, d=6Hz), 5.10(1H, s), 5.35(1H, 2, J=5.2Hz), 6.05(1H, dt,     J=6Hz, 15.5Hz), 6.46(1H, d, J=15,5Hz), 6.89(2H, d, J=9Hz), 7.18-8.09(6H,     m)

EXAMPLE 63

By using suitable starting materials, by a method similar to thatdescribed in Example 3, there were prepared compounds of Examples 1 and7-62.

EXAMPLE 64

By using suitable starting materials, by a method similar to thatdescribed in Example 5, there were prepared compounds of Examples 1 and7-15, and 17-62.

EXAMPLE 65

0.5 Gram of methyl 3-(4-hydroxyphenyl)-2(E)propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenpyridine-3,5-dicarboxylate wasdissolved in 5 ml of pyridine, then to this solution was added 0.5 ml ofacetic anhydride under an ice-cooling condition. The reaction mixturewas allowed to stand overnight, then poured into an ice-water, andextracted with ether. The ether layer was washed with a dilutedhydrochloric acid, 10%-sodium bicarbonate aqueous solution and water inthis order, then dried with anhydrous sodium sulfate. The ether extractwas concentrate, and the residue thus obtained was purified by means ofa silica gel column chromatography (eluent: methanol:chloroform=1:100)to yield 0.4 g of methyl 3-(4-acetyloxyphenyl)-2(E)propenyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate inthe form of light yellow indefinite form crystals.

NMR 2.28 (3H, s), 2.35 (6H, s), 3.64 (3H, s), 4.67 (2H, d, J=7Hz), 5.12(1H, s), 6.06 (1H, broad S), 6.15 (1H, d, t, Ja=7Hz, Jb=16Hz), 6.50 (1H,d, J=16Hz), 7.03 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 7.32 (1H, t,J=8Hz}, 7.63 (lH, dt, Ja=2Hz, Jb=8Hz), 7.97 (1H, d, t, Ja=2Hz, Jb=8Hz),8.12 (1H, t, J=2H)

EXAMPLE 66

50 Grams of 4-(1-ethoxyethoxy)cinnamyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine was dissolved in 600ml of tetrahydrofuran, the solution was cooled to 5° C., then 170 ml of0.5N-hydrochloric acid was added in one time to the solution. After 1hour, the temperature of the reaction mixture was kept at 10°-15° C.,and the reaction mixture was stirred for 2 hours. Sodium chloride wasadded to the reaction mixture and the aqueous layer was removed, the5%-sodium hydrogen carbonate aqueous solution was added to adjust the pHto 7.0-7.5. The aqueous layer was removed by separation, then theorganic layer was washed with water, a saturated sodium chloride aqueoussolution in the order, and dried with anhydrous magnesium sulfate. Thedried organic layer was concentrated at 20°-25° C., the residue thusobtained was recrystallized from chloroform to yield 20 g of(4-hydroxyphenyl)-2(E)-propenyl methyl 2,6 dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Melting point: 145.8°-149.4° C.

IR: 1670 cm⁻¹

In the above-mentioned Examples 66, the recrystallization was conductedby using ether in place of chloroform, there was yield(4-hydroxyphenyl)-2(E)-propenyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine3,5-dicarboxylatehaving the melting point of 163°-164° C.

IR: 1660 cm⁻¹, 1680 cm⁻¹.

EXAMPLE 67

3.0 Grams of 3-nitrobenzaldehyde, 2.3 g of methyl 3-aminocrotonate and 5g of methyl 4(E)-cinnamyloxyacetoacetate were suspended in 15 ml ofisopropanol, and the suspension was refluxed for 10 hours. After thereaction was finished, the solvent was removed by evaporation under areduced pressure, and the residue thus obtained was purified by means ofa silica gel column chromatography (eluent: ether:n-hexane=1:3 to 1:2).Recrystallization from ether to yield 4.0 g of 3,5-dimethyl2-cinnamyloxy-6-methyl-4-(3-nitrophenyl)-3,5-dicarboxylate in the formof light yellow powdery substance. Melting point: 121°-122° C.

By a method similar to that described in Example 67, and by usingsuitable starting materials, there were prepared compounds of Examples42-44.

EXAMPLE 68

5.1 Grams of 2-iodomethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate,and 3.8 g of 4-phenyl-1,2,3,6-tetrahydropyridine were dissolved in 10 mlof toluene, and the solution was refluxed for 6 hours. After thereaction mixture was allowed to stand to cooled at a room temperature,the crystals precipitated in the reaction mixture were removed byfiltration, the filtrate was concentrated and the residue thus obtainedwas dissolved in chloroform. The chloroform layer was washed with asaturated sodium hydrogen carbonate aqueous solution and water in thisorder, then dried with anhydrous sodium sulfate. Then the driedchloroform extract was concentrated by removing the solvent byevaporation, and the residue thus obtained was purified by means of asilica gel column chromatography (eluent: chloroform:methanol =300:1),and recrystallized from ethyl acetate-diisopropyl ether to yield 3.6 gof methyl 2-(4-phenyl-1,2,3,6-tetrahydropyridyl)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate inthe form of light yellow powdery substance. Melting point: 115°-116° C.

By a method similar to that described in Example 68, and by usingsuitable starting materials, there were prepared compounds of Examples47-59.

EXAMPLE 69

10.2 Grams of methyl 2-piperazinylethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of3-phenylpropargyl bromide in 100 ml of acetonitrile were stirred at 30°C. for 5 hours under heating condition. After the reaction was finished,chloroform was added to the reaction mixture, and the mixture was washedwith a saturated sodium hydrogen carbonate aqueous solution and water inthis order, and dried with anhydrous sodium sulfate. The driedchloroform extract was concentrated by removing the solvent byevaporation, the residue thus obtained was purified by means of a silicagel column chromatography (eluent:dichloromethane-methanol:dichloromethane =1:100). The product thuspurified was then converted into a hydrochloride by adding hydrochloricacid-dioxane, and recrystallized from ethyl acetate-methanol-water toyield 1.2 g of methyl 2-[4-(3-phenyl-2-propynyl)-1-piperazinyl]ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate inthe form of light yellow needle-like crystals. Melting point: 217°-220°C.

By a method similar to that described in Example 69, and by using asuitable starting material, there waa prepared a compound of Example 58.

PHARMACOLOGICAL TESTS

The results of the pharmacological test on dihydropyridine derivativesof the present invention are shown below.

The test compounds used in the tests are as

    ______________________________________                                        Test                                                                          Compound                                                                      No.                                                                           ______________________________________                                         1.     Methyl 3-(4-hydroxyphenyl)-2(E)-propenyl 1,4-                                 dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-                               3,5-dicarboxylate                                                      2.     Methyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-                                dimethyl-4-(3-nitrophenyl)pyridine-3,5-                                       dicarboxylate                                                          3.     Methyl 5-(4-hydroxyphenyl)-2(E),4(E)-pentadienyl                              1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                             4.     Methyl 3-methyl-3-(4-hydroxyphenyl)-2(E)-                                     propenyl 1,4-dihydro-2,6-dimethyl-4-(3-                                       nitrophenyl)pyridine-3,5-dicarboxylate                                 5.     Methyl 3-phenyl-2-propynyl 1,4-dihydro-2,6-                                   dimethyl-4-(3-nitrophenyl)pyridine-3,5-                                       dicarboxylate                                                          6.     Methyl 3-phenylpropyl 1,4-dihydro-2,6-                                        dimethyl-4-(3-nitrophenyl)pyridine-3,5-                                       dicarboxylate [Reference compound: Japanese                                   Patent Application Kokai (Laid-open) No.                                      56-36455 (1981)]                                                       7.     Methyl 3-(3-methoxy-4-hydroxyphenyl)-2(E)-                                    propenyl 1,4-dihydro-2,6-dimethyl-4-(3-                                       nitrophenyl)pyridine-3,5-dicarboxylate                                 8.     Methyl 3-(4-methoxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dihydrocarboxylate                                        9.     Methyl 3-(1-methyl-1,2,3,4-tetrazol-5-yl)-                                    2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-                                     (3-nitrophenyl)pyridine-3,5-dicarboxylate                             10.     Methyl 3-furyl-2(E)-propenyl 1,4-dihydro-                                     2,6-dimethyl-4-(3-nitrophenyl)pyridine-                                       3,5-dicarboxylate                                                     11.     Methyl 3-(3-chloro-4-hydroxyphenyl)-2(E)-                                     propenyl 1,4-dihydro-2,6-dimethyl-4-                                          (3-nitrophenyl)pyridine-3,5-dicarboxylate                             12.     Methyl 3-(4-hydroxyphenyl)-2-propynyl                                         1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                            13.     Methyl 3-(2-hydroxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                            14.     Methyl 3-(4-hydroxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-(2-trifluoro-                                      methylphenyl)pyridine-3,5-dicarboxylate                               15.     Methyl 4-(4-methylthiophenyl)-3(E)-butenyl                                    1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                            16.     Methyl 3-(4-acetyloxyphenyl)-2(E)-propenyl                                    1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                            17.     Methyl 2-[4-(4-methylphenyl)-1,2,3,6-tetra-                                   hydropyridyl]ethyl 1,4-dihydro-2,6-dimethyl-                                  4-(3-nitrophenyl)pyridine-3,5-dicarboxylate                           18.     Methyl 3-(4-hydroxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-phenylpyridine-                                    3,5-dicarboxylate                                                     19.     Methyl 3-(4-hydroxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-(2-methylphenyl)-                                  pyridine-3,5-dicarboxylate                                            20.     Methyl 3-(4-hydroxyphenyl)-2(E)-propenyl                                      1,4-dihydro-2,6-dimethyl-4-(3,4-dimethoxy-                                    phenyl)pyridine-3,5-dicarboxylate                                     21.     Dimethyl 1,4-dihydro-2-[3-(4-hydroxyphenyl)-                                  2(E)-propenyloxymethyl]-6-methyl-4-(3-                                        nitrophenyl)pyridine-3,5-dicarboxylate                                22.     Methyl 3-(2-thienyl)-2-propynyl 1,4-dihydro-                                  2,6-dimethyl-4-(3-nitrophenyl)pyridine-                                       3,5-dicarboxylate                                                     23.     Methyl 2-[4-(3-phenyl-2-propynyl)-1-                                          piperazinyl]ethyl 1,4-dihydro-2,6-dimethyl-                                   4-(3-nitrophenyl)pyridine-3,5-dicarboxylate                           24.     Methyl 3-(4-hydroxyphenyl)-2(E)propenyl                                       1,4-dihydro-2,6-dimethyl-4-(2,4-dichloro-                                     phenyl)pyridine-3,5-dicarboxylate                                     25.     Methyl 3-(3-hydroxyphenyl)-2(E)propenyl                                       1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-                                   pyridine-3,5-dicarboxylate                                            26.     Methyl 2-(N-methyl-N-benzylamino)ethyl 1,4-                                   dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-                           dicarboxylate [Reference compound known as                                    "Nicardipine")                                                        ______________________________________                                    

PHARMACOLOGICAL TEST-1

Vasodilative effects of the dihydropyridine derivatives of the presentinvention were determined by measuring the systolic blood pressures oftest animals before and after the administration of test compound.

Systolic blood pressures and heart beat of SHR-rats (spontaneouslyhypertensive rats) were determined by a "tail cuff method". Thus thetest animal was placed in a thermostat chamber (Type: FR-12RS,manufactured by Isuze & Co.) and was warmed at 40° C. for 15 minutes soas to vasodilate the tail arteria, the systolic blood pressures weremeasured by an electro sphygmomanometer (Type: PE-300, manufactured byNarco-Biosystems, Inc.) and recorded by an ink-writing recorder (Type:RECTI-HORIZ 8s, manufactured by San-Ei Instrument & Co.). Theexperiments were conducted under non-anesthetized and semi-confinementconditions. The test compound was orally administered forcedly by usinga sonde for oral administration. The test compound was suspended in0.15%-gum arabic powder aqueous solution so as to make the quantity ofthe test compound to 2.5 ml/kg. The test animal was not fasted, and thesystolic blood pressures (mm-Hg) were measured before the administration(hereinafter referred to as "PRE") and after the administration (8, 24,30, 48, 54 and 72 hours after the administration) of the test compound.The data of systolic blood pressure measured before the administrationare shown in absolute value of mmHg, and the data measured after theadministration are shown in the differences from the absolute values.The results are shown in Table 2 as follows.

                                      TABLE 2                                     __________________________________________________________________________    Test  Dosage  Blood pressure (mm-Hg)                                          Compound                                                                            (mg/kg) After the administration (Hours)                                No.   p.o. PRE                                                                              8   24  30  48  54  72                                          __________________________________________________________________________    1     30   195.0                                                                            --  -41.0                                                                             -52.0                                                                             -26.5                                                                             -19.8                                                                             -12.5                                       2     30   187.4                                                                            --  -38.6                                                                             -21.2                                                                             -21.0                                                                             -19.2                                                                             --                                          3     30   180.8                                                                            --  -31.0                                                                             -30.8                                                                             -15.6                                                                             -12.6                                                                             --                                          4     30   184.4                                                                            --  -18.0                                                                             -25.8                                                                             -19.8                                                                             -14.6                                                                             --                                          5     30   180.8                                                                            --  -75.4                                                                             -66.8                                                                             -20.8                                                                             -10.6                                                                              -9.6                                       6     30   185.0                                                                            -20.3                                                                              +1.8                                                                             --  --  --  --                                          __________________________________________________________________________

As can be seen the data shown in Table 2, the vasodilative effects ofthe dihydropyridine derivatives of the present invention can beprolonged for certain length of period as compared with that of thereference compounds.

PHARMACOLOGICAL TESTS

Calmodulin (calcium-dependent modulator protein inhibitory activity ofeach of the test compounds was determined by judging from the differencebetween IC₅₀ (50%-inhibitory concentration) of calmodulin inhibitoryactivity of the test compound being measured in the presence ofcalmodulin together with calmodulin-dependent cyclic-AMPphosphodiesterase, and another IC₅₀ of calmodulin-dependent cyclic-AMPphosphodiesterase inhibitory activity of the same test compound beingmeasured in the absence of calmodulin. In other words,calmodulin-specific-inhibitory activity of each of the test compoundswas determined in case that the test compound shows higher inhibitoryactivity against calmodulin-dependent cyclic-AMP phosphodiesterase inthe presence of calmodulin than another inhibitory activity againstcalmodulin-dependent cyclic-AMP phosphodiesterase only.

1) Reagents used in the test

(1) Calmodulin: A calmodulin product manufactured by Amano & Co., whichwas isolated from the brain of bovine, and purified so as to beconsidered as a single substance with respect to SDS-page(polyacrylamide gel electrophoresis) method.

(2) Calmodulin-dependent cyclic-AMP phosphodiesterase (EC 3.1.4.17): Anenzyme substance isolated from the heart of bovine and purifiedpartially by a method of modified version of the disclosure in H. C. Ho,T. S. Teo, et al.: "Biochim. Biophys. Acta", 429, 461 (1976).

(3) 5'-Nucleotidase (EC 3.1.3.5): Grade IV substance (isolated fromCrotalus adamanteus venom) manufactured by Sigma & Co.

(4) Others: Remainder of the reagents used in the test were those ofreagent grade chemicals manufactured by Wako Pure-Chemical Industries,Ltd.

2) Method for the test

Calmodulin inhibitory activity of each of the test compounds wasmeasured by a method of modified version of the disclosure in T. S. Teoand T. H. Wang: "J. Bio. Chem.", 248, 588 (1973).

(1) Cyclic-AMP-phosphodiesterase: One unit thereof hydrolyzes 1.0micromole of 3':5'-cyclic-AMP to 5'-AMP per minute at pH 7.5 at 30° C.,in the presence of a saturating level of calmodulin.

(2) Calmodulin: One unit thereof stimulates 0.015 activated unit ofcyclic-AMP phosphodiesterase to 50% of the maximum activity of theenzyme.

(3) 5'-Nucleotidase: One unit thereof hydrolyzes 1.0 micromole ofinorganic phosphorus from adnosine 5'-monophosphate per minute at pH 9.0at 37° C.

3) Reactions in the tests

(1) Calmodulin-cyclic-AMP phosphodiesterase inhibitory activity:

40 mM of Imidazol, 20 mM of MgCl₂, 20 mM of CaC12, 0.008 unit ofcyclic-AMP phosphodiesterase, 1.0 unit of calmodulin, 0.2 unit of5'-nucleotidase and 1.0 ml of 10 mM-tris(hydroxymethyl)aminomethane/HClbuffer solution (pH 7.0) containing 0.5 mM of cyclic-AMP were mixedtogether, and reacted at 30° C. for 30 minutes. Each of the testcompounds was dissolved in methanol or N,N-dimethylformamide as thesolvent, provided that the quantity of the solvent was not exceed 2% ofthe total amount of the mixture. After the reaction was completed, thereaction mixture was ice-cooled, and 0.5 ml each of aqueous solutions of16.5%-trichloroacetic acid, 1%-thiourea, 3%-ammonium ferrous sulfatewere respectively added to the reaction mixture. Further, 0.15 ml of4.4%-ammonium molibdate solution was added to the mixture and the wholeof the mixture was stirred, and was centrifuged at 3,000 r.p.m. for 10minutes. Then, the centrifuged mixture was allowed to stand at a roomtemperature for 20 minutes. The OD₆₆₀ nm (optical density at 660 nm) wasmeasured.

(2) Cyclic AMP phosphodiesterase inhibitory activity:

The reaction was conducted by a method similar to that described in (1)as mentioned above, except that 1 mM of EGTA [ethyleneglycol-bis(β-amino ethyl ether)-N,N-tetraacetic acid] was used in placeof 20 mM of CaCl₂. The reaction was conducted for 3 hours. The resultsare shown in Table 3 as follows.

                  TABLE 3                                                         ______________________________________                                        Test    Calmodulin-cyclic-AMP                                                                         Cyclic-AMP                                            Compound                                                                              phosphodiesterase IC.sub.50                                                                   phosphodiesterase IC.sub.50                           No.     (μg/ml)      (μg/ml)                                            ______________________________________                                         1      4.1             60                                                     2      2.5             >100                                                   3      0.85            >100                                                   7      5.2             86                                                     8      2.7             >100                                                   9      5.3             36                                                    10      1.55            >100                                                  11      5.3             100                                                   12      0.78            13                                                    13      1.65            12.5                                                  14      6.25            >100                                                  15      0.062           0.23                                                  16      3.0             50                                                    17      5.5             >100                                                  18      6.8             32                                                    19      5.8             58                                                    20      3.2             30                                                    21      6               >100                                                  22      1.1             >100                                                  23      8.0             >100                                                  24      2.45            15                                                    25      0.9             24.6                                                  26      6.25            13                                                    ______________________________________                                    

As can be seen from the data shown in Table 3. the dihydropyridinederivatives of the present invention have specific inhibitory activityagainst calmodulin as compared with that of indicated by known compound.

What is claimed is:
 1. A dihydropyridine compound or a salt thereof ofthe formula ##STR149## wherein R¹ and R⁴ are each a lower alkyl group;R² is a lower alkyl group or a group of the formula--CH₂ --A--R⁶,wherein A is a straight-chain or branched-chain unsaturated hydrocarbongroup having 1 to 3 double bonds or one triple bond therein which mayhave an oxygen atom or a group of the formula ##STR150## in the chain,wherein R⁷ is a lower alkyl group, and R⁶ is a phenyl group which mayhave a hydroxy group as a substituent; R³ is a phenyl group which mayhave 1 to 2 substituents selected from the group consisting of a nitrogroup, a lower alkyl group which may have 1 to 3 halogen atoms, a loweralkoxy group and a halogen atom; and R⁵ is a lower alkyl group, a1,2,3,6-tetrahydropyridyl-lower alkyl group which may have, as asubstituent on the pyridyl ring, a phenyl group which may have halogenatoms or lower alkyl groups as substituents on the phenyl ring, or agroup of the formula --CH₂ --A'-R⁸, wherein A' is a straight-chain orbranched-chain unsaturated hydrocarbon group having 1 to 3 double bondsor one triple bond therein which may have an oxygen atom, a sulfur atom,a group of the formula ##STR151## wherein R⁷ is a lower alkyl group, ora group of the formula ##STR152## in the chain of the unsaturatedhydrocarbon group and R⁸ is a phenyl group which may have 1 to 3substituents selected from the group consisting of a lower alkoxy group,a halogen atom, a lower alkylthio group, a hydroxyl group, a loweralkanoyloxy group, a tetrahydropyranyloxy group and a lower alkoxy-loweralkoxy group, a pyridyl group, a thienyl group, a furyl group, or atetrazolyl group which may have a lower alkyl group as a substituent;provided that when R⁵ is a lower alkyl group, then R² should be a groupof the formula --CH₂ --A--R⁶.
 2. The dihydropyridine compounds of claim1, wherein R² is a group of the formula --CH₂ --A--R⁶, wherein A is astraight-chain or branched-chain unsaturated hydrocarbon group having 2to 6 carbon atoms in the unsaturated hydrocarbon moiety and having 1 to3 double bonds or one triple bond therein, which group may have anoxygen atom or a group of the formula ##STR153## in the chain, and R⁶ isa phenyl group which may have a hydroxy group as a substituent.
 3. Thedihydropyridine compounds of claim 2 wherein R⁵ is a group of theformula --CH₂ --A'--R⁸, wherein A' is a straight-chain or branched-chainunsaturated hydrocarbon group having 2 to 6 carbon atoms in theunsaturated hydrocarbon moiety and having 1 to 3 double bonds or onetriple bond therein, which group may have an oxygen atom, a sulfur atom,a group of the formula ##STR154## wherein R⁷ is a C₁₋₆ -alkyl group, ora group of the formula ##STR155## in the chain of the unsaturatedhydrocarbon group.
 4. The dihydropyridine compounds of claim 3, whereinA' is a straight-chain or branched-chain unsaturated hydrocarbon grouphaving 2 to 6 carbon atoms in the unsaturated hydrocarbon moiety, whichhas an oxygen atom, a sulfur atom, a group of the formula ##STR156## ora group of the formula ##STR157## in the chain.
 5. The dihydropyridinecompounds of claim 3, wherein A' is a straight-chain or branched-chainunsaturated hydrocarbon group having 2 to 6 carbon atoms in theunsaturated hydrocarbon moiety, which does not have an oxygen atom, asulfur atom, a group of the formula ##STR158## or a group of the formula##STR159## in the chain in the unsaturated hydrocarbon group.
 6. Thedihydropyridine compounds of claim 1 wherein R² is an alkyl group having1 to 6 carbon atoms.
 7. The dihydropyridine compounds of claim 2 whereinR⁵ is an alkyl group having 1 to 6 carbon atoms.
 8. The dihydropyridinecompounds of claim 6, wherein R⁵ is a 1,2,3,6-tetrahydropyridyl-C₁₋₆-alkyl group which may have, as the substituent on the pyridyl ring, aphenyl group which may have halogen atoms or lower alkyl groups as thesubstituents on the phenyl ring.
 9. The dihydropyridine compounds ofclaim 2, wherein R⁵ is a 1,2,3,6-tetrahydropyridyl-C₁₋₆ -alkyl groupwhich may have, as the substituent on the pyridyl ring, a phenyl groupwhich may have halogen atoms or C₁₋₆ -alkyl groups as the substituentson the phenyl ring; or a group of the formula --CH₂ --A'--R⁸.
 10. Thedihydropyridine compounds of claim 4, wherein R⁸ is a phenyl group whichmay have 1 to 3 substituents on the phenyl ring, selected from the groupconsisting of a C₁₋₆ -alkoxy group, a halogen atom, a C₁₋₆ -alkylthiogroup, a hydroxyl group, C₁₋₆ -alkanoyloxy group, a tetrahydropyranyloxygroup and a C₁₋₆ -alkoxy-C₁₋₆ -alkoxy group.
 11. The dihydropyridinecompounds claim 5, wherein R⁸ is a phenyl group which may have 1 to 3substituents on the phenyl ring, selected from the group consisting of aC₁₋₆ -alkoxy group, a halogen atom, a C₁₋₆ -alkylthio group, a hydroxylgroup, a C₁₋₆ -alkanoyloxy group, a tetrahydropyranyloxy group and aC₁₋₆ -alkoxy-C₁₋₆ -alkoxy group.
 12. The dihydropyridine compounds ofclaim 4 or 5, wherein R⁸ is a pyridyl group, a thienyl group, a furylgroup, or a tetrazolyl group which may have a lower alkyl group as thesubstituent.
 13. The dihydropyridine compounds of claim 11, wherein R⁸is a phenyl group which may have 1 to 3 substituents on the phenyl ring,selected from the group consisting of a hydroxyl group and C₁₋₆-alkanoyloxy group.
 14. The dihydropyridine compounds of claim 11,wherein R⁸ is a phenyl group which contains 1 to 3 substituents on thephenyl ring, selected from the group consisting of a C₁₋₆ -alkoxy group,a halogen atom, a C₁₋₆ -alkylthio group, a tetrahydropyranyloxy groupand C₁₋₆ -alkoxy-C₁₋₆ -alkoxy group.
 15. The dihydropyridine compoundsof claim 13 or 14, wherein R³ is a phenyl group which may have 1 to 2nitro groups as substituents on the phenyl ring.
 16. The dihydropyridinecompounds of claim 13 or 14, wherein R³ is a phenyl group having 1 to 2C₁₋₆ -alkyl groups as substituents on the phenyl ring, said C₁₋₆ -alkylgroups containing 1 to 3 halogen atoms as substituents.
 17. Thedihydropyridine compounds of claims 13 or 14, wherein R³ is a phenylgroup having 1 to 2 substituents on the phenyl ring, selected from thegroup consisting of a C₁₋₆ -alkyl group, a C₁₋₆ -alkoxy group and ahalogen atom.
 18. The dihydropyridine compounds of claim 15, wherein thestraight-chain or branched-chain unsaturated hydrocarbon group is astraight-chain or branched-chain unsaturated hydrocarbon group whichonly contains 1-3 double bonds.
 19. The dihydropyridine compoundsaccording to claim 15, wherein the straight-chain or branched-chainunsaturated hydrocarbon group is a straight-chain or branched-chainunsaturated hydrocarbon group which only contains 1 triple bond.
 20. Thedihydropyridine compounds of claim 13, wherein R⁸ is an unsubstitutedphenyl group.
 21. The dihydropyridine compounds of claim 13, wherein R⁸is a phenyl group which has 1 to 3 substituents, on the phenyl ring,selected from the group consisting of a hydroxyl group and a C₁₋₆alkanoyloxy group.
 22. The dihydropyridine compounds of claim 20 or 21,wherein R³ is a phenyl group which may have 1 to 2 nitro groups assubstituents on the phenyl ring.
 23. The dihydropyridine compounds ofclaim 20 or 21, wherein R³ is a phenyl group having 1 to 2 C₁₋₆ alkylgroups as substituents on the phenyl ring, said C₁₋₆ alkyl groupscontaining 1 to 3 halogen atoms as substituents.
 24. The dihydropyridinecompounds of claim 20 or 21, wherein R³ is a phenyl group having 1 to 2substituents on the phenyl ring, selected form the group consisting of aC₁₋₆ group, a C₁₋₆ alkoxy group and a halogen atom.
 25. Thedihydropyridine compounds of claim 20 or 21, wherein the straight-chainor branched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated group containing 1 to 3 double bonds.
 26. Thedihydropyridine compounds of claim 20 or 21, wherein the straight-chainor branched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated group containing 1 to triple bond.
 27. Thedihydropyridine compounds of claim 1, wherein R² is a C₁ -C₆ alkylgroup; R³ is a phenyl group which may have 1 to 2 substituents selectedfrom the group consisting of a nitro group, a C₁ -C₆ alkyl group whichmay have 1 to 3 halogen atoms, a C₁ -C₆ alkoxy group and a halogen atom;and R⁵ is a 1,2,3,6-tetrahydropyridyl-C₁ -C₆ alkyl group which may have,as the substituents, a phenyl group which may have halogen atoms or C₁-C₆ alkyl groups as the substituents on the phenyl ring, or a group ofthe formula --CH₂ --A'--R⁸, wherein A' is a straight-chain orbranched-chain unsaturated hydrocarbon group having 2 to 6 carbon atomsin the unsaturated hydrocarbon moiety and having 1 to 3 double bonds orone triple bond therein; and R⁸ is a phenyl group, which may have 1 to 3substituents selected from the group consisting of a C₁ -C₆ alkoxygroup, a halogen atom, a C₁ -C₆ alkylthio group, a hydroxyl group, a C₁-C₆ alkanoyloxy group, a tetrahydropyranyloxy group and a C₁ -C₆alkoxy-C₁ -C₆ alkoxy group, a pyridyl group, a thienyl group, a furylgroup, or a tetrazolyl group, which may have a C₁ -C₆ alkyl group as asubstituent.
 28. The dihydropyridine compounds of claim 27, wherein R⁵is a 1,2,3,6-tetrahydropyridyl-C₁₋₆ -alkyl group which may have, as asubstituent on the pyridyl ring, a phenyl group which may have halogenatoms or C₁₋₆ alkyl groups as substituents on the phenyl ring.
 29. Thedihydropyridine compounds of claim 27, wherein R⁵ is a group of theformula --CH₂ --A'--R⁸.
 30. The dihydropyridine compounds of claim 29,wherein R⁸ is a phenyl group which may have 1 to 3 substituents on thephenyl ring selected from the group consisting of a C₁₋₆ -alkoxy group,a halogen atom, a C₁₋₆ -alkylthio group, a hydroxyl group, C₁₋₆-alkanoyloxy group, a tetrahydropyranyloxy group and a C₁₋₆ -alkoxy-C₁₋₆-alkoxy group.
 31. The dihydropyridine compounds of claim 29, wherein R⁸is a pyridyl group, a thienyl group, a furyl group, or a tetrazolylgroup which may have a C₁ -C₆ alkyl group as a substituent.
 32. Thedihydropyridine compounds of claim 30, wherein R⁸ is a phenyl groupwhich may have 1 to 3 substituents on the phenyl ring selected from thegroup consisting of a hydroxyl group and C₁₋₆ -alkanoyloxy group. 33.The dihydropyridine compounds of claim 30, wherein R⁸ is a phenyl groupwhich contains 1 to 3 substituents on the phenyl ring selected from thegroup consisting of a C₁₋₆ -alkoxy group, a halogen atom, a C₁₋₆-alkylthio group, a tetrahydropyranyloxy group and a C₁₋₆ -alkoxy-C₁₋₆-alkoxy group.
 34. The dihydropyridine compounds of claim 32 or 33,wherein R³ is a phenyl group which may have 1 to 2 nitro groups assubstituents on the phenyl ring.
 35. The dihydropyridine compounds ofclaim 32 or 33, wherein R³ is a phenyl group having 1 to 2 C₁₋₆ -alkylgroups as substituents on the phenyl ring, said C₁₋₆ -alkyl groupcontaining 1 to 3 halogen atoms as substituents.
 36. The dihydropyridinecompounds of claim 32 or 33, wherein R³ is a phenyl group having 1 to 2substituents on the phenyl ring, selected from the group consisting of aC₁₋₆ -alkyl group, a C₁₋₆ -alkoxy group and a halogen atom.
 37. Thedihydropyridine compounds of claim 34, wherein the straight-chain orbranched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated hydrocarbon group which only contains 1-3double bonds.
 38. The dihydropyridine compounds of claim 34, wherein thestraight-chain or branched-chain unsaturated hydrocarbon group isstraight-chain or branched-chain unsaturated hydrocarbon group whichonly contains 1 triple bond.
 39. The dihydropyridine compounds of claim32, wherein R⁸ is an unsubstituted phenyl group.
 40. The dihydropyridinecompounds of claim 32, wherein R⁸ is a phenyl group which has 1 to 3substituents, on the phenyl ring, selected from the group consisting ofa hydroxy group and a C₁₋₆ alkanoyloxy group.
 41. The dihydropyridinecompounds of claim 39 or 40, wherein R³ is a phenyl group which may have1 to 2 nitro groups as substituents on the phenyl ring.
 42. Thedihydropyridine compounds of claim 39 or 40, wherein R³ is a phenylgroup having 1 to 2 C₁₋₆ alkyl groups as substituents on the phenylring, said C₁₋₆ alkyl group containing 1 to 3 halogen atoms assubstituents.
 43. The dihydropyridine compounds of claim 39 or 40,wherein R³ is a phenyl group having 1 to 2 substituents on the phenylring, selected from the group consisting of a C₁₋₆ alkyl group, a C₁₋₆alkoxy group and a halogen atom.
 44. The dihydropyridine compounds ofclaim 39 or 40, wherein the straight-chain or branched-chain unsaturatedhydrocarbon group is a straight-chain or branched-chain unsaturatedgroup containing 1 to 3 double bonds.
 45. The dihydropyridine compoundsof claim 39 or 40, wherein the straight-chain or branched-chainunsaturated hydrocarbon group is a straight-chain or branched-chainunsaturated group containing 1 triple bond.
 46. A hypotensivecomposition containing, as the active ingredient, an effective amount ofa dihydropyridine compound of claim 27 and a pharmaceutically acceptablecarrier.
 47. A coronary vasodilator composition containing, as theactive ingredient, an effective amount of a dihydropyridine compound ofclaim 27 and a pharmaceutically acceptable carrier.
 48. Thedihydropyridine compounds of claim 1, wherein R² is a C₁ -C₆ alkylgroup; R³ is a phenyl group which may have 1 to 2 substituents selectedfrom the group consisting of a nitro group, a C₁ -C₆ alkyl group whichmay have 1 to 3 halogen atoms, a C₁ -C₆ alkoxy group and a halogen atom;and R⁵ is a group of the formula --CH₂ --A'--R⁸, wherein A' is astraight-chain or branched-chain unsaturated hydrocarbon group having 2to 6 carbon atoms in the unsaturated hydrocarbon moiety and having 1 to3 double bonds or triple bond therein, which has an oxygen atom, asulfur atom, a group of the formula ##STR160## wherein R⁷ is a C₁ -C₆alkyl group, or a group of the formula ##STR161## in the chain of theunsaturated hydrocarbon group and R⁸ is a phenyl group which may have 1to 3 substituents selected from the group consisting of a C₁ -C₆ alkoxygroup, a halogen atom, a C₁ -C₆ alkylthio group, a hydroxyl group; a C₁-C₆ alkanoyloxy group, a tetrahydropyranyloxy group and a C₁ -C₆alkoxy-C₁ -C₆ alkoxy group; a pyridyl group, a thienyl group, a furylgroup, or a tetrazolyl group, which may have a C₁ -C₆ alkyl group as asubstituent.
 49. The dihydropyridine compounds of claim 48, wherein A'is a straight-chain or branched-chain unsaturated hydrocarbon grouphaving 2 to 6 carbon atoms in the unsaturated hydrocarbon moiety andhaving 1 to 3 double bonds or one triple bond therein, which has anoxygen atom, a sulfur atom, or a group of the formula ##STR162## in thechain of the unsaturated hydrocarbon group.
 50. The dihydropyridinecompounds of claim 48, wherein A' is a straight-cain or branched-chainunsaturated hydrocarbon group having 2 to 6 carbon atoms in theunsaturated hydrocarbon moiety and having 1 to 3 double bonds or onetriple bond therein, which has a group of the formula ##STR163## in thechain of the unsaturated hydrocarbon group.
 51. The dihydropyridinecompounds of claim 49 or 50, wherein R⁸ is a phenyl group which may have1 to 3 substituents on the phenyl ring, selected from the groupconsisting of a C₁ -C₆ -alkoxy group, a halogen atom, a C₁ -C₆-alkylthio group, a hydroxyl group, C₁ -C₆ -alkanoyloxy group, atetrahydropyranyloxy group and a C₁ -C₆ -alkoxy-C ₁ -C₆ -alkoxy group.52. The dihydropyridine compounds of claim 49 or 50, wherein R⁸ is apyridyl group, a thienyl group, a furyl group, or a tetrazolyl groupwhich may have a C₁ -C₆ alkyl group as a substituent.
 53. Thedihydropyridine compounds of claim 51, wherein R⁸ is a phenyl groupwhich may have 1 to 3 substituents on the phenyl ring, selected from thegroup consisting of a hydroxyl group and a C₁ -C₆ -alkanoyloxy group.54. The dihydropyridine compounds of claim 51, wherein R⁸ is a phenylgroup which contains 1 to 3 substituents on the phenyl ring, selectedfrom the group consisting of a C₁₋₆ -alkoxy group, a halogen atom, aC₁₋₆ -alkylthio group, a tetrahydropyranyloxy group and a C₁₋₆-alkoxy-C₁₋₆ -alkoxy group.
 55. The dihydropyridine compounds of claim53, wherein R³ is a phenyl group which may have 1 to 2 nitro groups assubstituents on the phenyl ring.
 56. The dihydropyridine compounds ofclaim 54, wherein R³ is a phenyl group which may have 1 to 2 nitrogroups as substituents on the phenyl ring.
 57. The dihydropyridinecompounds of claim 53, wherein R³ is a phenyl group having 1 to 2 C₁₋₆-alkyl groups as substituents on the phenyl ring, said C₁₋₆ -alkyl groupcontaining 1 to 3 halogen atoms as substituents.
 58. The dihydropyridinecompounds of claim 54, wherein R³ is a phenyl group having 1 to 2 C₁₋₆-alkyl groups as substituents on the phenyl ring, said C₁₋₆ -alkyl groupcontaining 1 to 3 halogen atoms as substituents.
 59. The dihydropyridinecompounds of claim 53, wherein R³ is a phenyl group having 1 to 2substituents on the phenyl ring, selected from the group consisting of aC₁₋₆ -alkyl group, a C₁₋₆ -alkoxy group and a halogen atom.
 60. Thedihydropyridine compounds of claim 54, wherein R³ is a phenyl grouphaving 1 to 2 substituents on the phenyl ring, selected from the groupconsisting of a C₁₋₆ -alkyl group, a C₁₋₆ -alkoxy group and a halogenatom.
 61. The dihydropyridine compounds of claim 55, wherein thestraight-chain or branched-chain unsaturated hydrocarbon group is astraight-chain or branched-chain unsaturated hydrocarbon group whichonly contains 1-3 double bonds.
 62. The dihydropyridine compounds ofclaim 56, wherein the straight-chain or branched-chain unsaturatedhydrocarbon group is a straight-chain or branched-chain unsaturatedhydrocarbon group which only contains 1-3 double bonds.
 63. Thedihydropyridine compounds of claim 55, wherein the straight-chain orbranched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated hydrocarbon group which only contains 1triple bond.
 64. The dihydropyridine compounds of claim 56, wherein thestraight-chain or branched-chain unsaturated hydrocarbon group is astraight-chain or branched-chain unsaturated hydrocarbon group whichonly contains 1 triple bond.
 65. The dihydropyridine compounds of claim53, wherein R⁸ is an unsubstituted phenyl group.
 66. The dihydropyridinecompounds of claim 53, wherein R⁸ is a phenyl group which has 1 to 3substituents, on the phenyl ring, selected from the group consisting ofa hydroxy group and C₁₋₆ alkanoyloxy group.
 67. The dihydropyridinecompounds of claim 65, wherein R³ is a phenyl group which may have 1 to2 nitro groups as substituents on the phenyl ring.
 68. Thedihydropyridine compounds of claim 66, wherein R³ is a phenyl groupwhich may have 1 to 2 nitro groups as substituents on the phenyl ring.69. The dihydropyridine compounds of claim 65, wherein R³ is a phenylgroup having 1 to 2 C₁₋₆ alkyl groups as substituents on the phenylring, said C₁₋₆ alkyl group containing 1 to 3 halogen atoms assubstituents.
 70. The dihydropyridine compounds of claim 66, wherein R³is a phenyl group having 1 to 2 C₁₋₆ alkyl groups as substituents on thephenyl ring, said C₁₋₆ alkyl group containing 1 to 3 halogen atoms assubstituents.
 71. The dihydropyridine compounds of claim 65, wherein R³is a phenyl group having 1 to 2 substituents on the phenyl ring,selected from the group consisting of a C₁₋₆ alkyl group, a C₁₋₆ alkoxygroup and a halogen atom.
 72. The dihydropyridine compounds of claim 66,wherein R³ is a phenyl group having 1 to 2 substituents on the phenylring, selected from the group consisting of a C₁₋₆ alkyl group, a C₁₋₆alkoxy group and a halogen atom.
 73. The dihydropyridine compounds ofclaim 65, wherein the straight-chain or branched-chain unsaturatedhydrocarbon group is a straight-chain or branched-chain unsaturatedhydrocarbon group containing 1-3 double bonds.
 74. The dihydropyridinecompounds of claim 66, wherein the straight-chain or branched-chainunsaturated hydrocarbon group is a straight-chain or branched-chainunsaturated hydrocarbon group containing 1-3 double bonds.
 75. Thedihydropyridine compounds of claim 65, wherein the straight-chain orbranched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated group containing 1 triple bond.
 76. Thedihydropyridine compounds of claim 66, wherein the straight-chain orbranched-chain unsaturated hydrocarbon group is a straight-chain orbranched-chain unsaturated group containing 1 triple bond.
 77. Ahypotensive composition containing, as the active ingredient, aneffective amount of a dihydropyridine compound of claim 48 and apharmaceutically acceptable carrier.
 78. A coronary vasodilatorcomposition containing, as the active ingredient, a dihydropyridinecompound of claim 48 and a pharmaceutically acceptable carrier.
 79. Thedihydropyridine compounds of claim 1, wherein R² is a group of theformula --CH₂ --A--R⁶, wherein A is a straight-chain or branched-chainunsaturated hydrocarbon group having 2 to 6 carbon atoms in theunsaturated hydrocarbon moiety and having 1 to 3 double bonds or onetriple bond therein, which group may have an oxygen atom or a group ofthe formula ##STR164## in the chain, wherein R⁷ is a C₁ -C₆ alkyl group,and R⁶ is a phenyl group which may have a hydroxyl group as asubstituent; R³ is a phenyl group which may have 1 to 2 substituentsselected from the group consisting of a nitro group, a C₁ -C₆ alkylgroup which may have 1 to 3 halogen atoms, a C₁ -C₆ alkoxy group and ahalogen atom; and R⁵ is a C₁ -C₆ alkyl group, a1,2,3,6-tetrahydropyridyl-C₁ -C₆ alkyl group which may have, as asubstituent on the pyridyl ring, a phenyl group which may have halogenatoms or C₁ -C₆ alkyl groups as substituents on the phenyl ring, or agroup of the formula --CH₂ --A'--R⁸ wherein A' is a straight-chain orbranched-chain unsaturated hydrocarbon group having 2 to 6 carbon atomsin the unsaturated hydrocarbon moiety and having 1 to 3 double bonds orone triple bond therein, which group may have an oxygen atom, a sulfuratom, a group of the formula ##STR165## wherein R⁷ is a C₁ -C₆ alkylgroup, or a group of the formula ##STR166## in the chain of theunsaturated hydrocarbon group and R⁸ is a phenyl group which may have 1to 3 substituents selected from the group consisting of a C₁ -C₆ alkoxygroup, a halogen atom, a C₁ -C₆ alkylthio group, a hydroxyl group; a C₁-C₆ alkanoyloxy group, a tetrahydropyranyloxy group and a C₁ -C₆alkoxy-C₁ -C₆ alkoxy group, a pyridyl group, a thienyl group, a furylgroup, or a tetrazolyl group which may have a C₁ -C₆ alkyl group as asubstituent.
 80. The dihydropyridine compounds of claim 79, wherein R⁵is an alkyl group having 1 to 6 carbon atoms.
 81. The dihydropyridinecompounds of claim 79, wherein R⁵ is a 1,2,3,6-tetrahydropyridyl-C₁₋₆-alkyl group which may have, as the substituent on the pyridyl ring, aphenyl group which may have halogen atoms or C₁₋₆ -alkyl groups as thesubstituents on the phenyl ring or a group of the formula --CH₂--A'--R⁸.
 82. A hypotensive composition containing, as the activeingredient, an effective amount of a dihydropyridine compound of claim79 and a pharmaceutically acceptable carrier.
 83. A coronary vasodilatorcomposition containing, as the active ingredient, an effective amount ofa dihydropyridine compound of claim 79 and a pharmaceutically acceptablecarrier.
 84. A hypotensive composition containing, as the activeingredient an effective amount of a dihydropyridine compound of claim 1and a pharmaceutically acceptable carrier.
 85. A coronary vasodilatorcomposition containing, as the active ingredient an effective amount ofa dihydropyridine compound of claim 1 and a pharmaceutically acceptablecarrie.